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Sample records for cerebellar purkinje neurons

  1. Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses.

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    Sudhakar, Shyam Kumar; Torben-Nielsen, Benjamin; De Schutter, Erik

    2015-12-01

    Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.

  2. l-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

    OpenAIRE

    Furuya, Shigeki; Tabata, Toshihide; Mitoma, Junya; Yamada, Keiko; Yamasaki, Miwako; Makino, Asami; Yamamoto, Toshifumi; Watanabe, Masahiko; Kano, Masanobu; Hirabayashi, Yoshio

    2000-01-01

    Glial cells support the survival and development of central neurons through the supply of trophic factors. Here we demonstrate that l-serine (l-Ser) and glycine (Gly) also are glia-derived trophic factors. These amino acids are released by astroglial cells and promote the survival, dendritogenesis, and electrophysiological development of cultured cerebellar Purkinje neurons. Although l-Ser and Gly are generally classified as nonessential amino acids, 3-phosphoglyce...

  3. Inverse Stochastic Resonance in Cerebellar Purkinje Cells

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    Häusser, Michael; Gutkin, Boris S.; Roth, Arnd

    2016-01-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  4. Inverse Stochastic Resonance in Cerebellar Purkinje Cells.

    Science.gov (United States)

    Buchin, Anatoly; Rieubland, Sarah; Häusser, Michael; Gutkin, Boris S; Roth, Arnd

    2016-08-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  5. Differential sensitivity of cerebellar purkinje neurons to ethanol in selectively outbred lines of mice: maintenance in vitro independent of synaptic transmission.

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    Basile, A; Hoffer, B; Dunwiddie, T

    1983-03-28

    The effects of ethanol on spontaneous firing of cerebellar Purkinje neurons were examined in outbred lines of mice (short-sleep, SS; and long-sleep, LS) which exhibit differential behavioral sensitivity to ethanol. In order to determine whether the differences in Purkinje cell ethanol sensitivity which are observed in situ reflect differences in intrinsic properties of Purkinje neurons, we developed an isolated in vitro preparation of mouse cerebellum. Even when synaptic transmission was largely inhibited by elevating Mg2+ and decreasing Ca2+ concentrations, Purkinje cells demonstrated stable long-term firing rates quite similar to those observed in vivo. Purkinje cells responded to superfusion of ethanol with both increases and decreases in firing rate. Inhibition of rate was more commonly observed, and was the only response which was demonstrably dose-dependent. The differential sensitivity to ethanol which we have previously reported in vivo was maintained even under under these conditions, with the LS mice being approximately 5 times more sensitive to the depressant effects of ethanol. In addition, it was shown that ethanol, at the concentrations used in these experiments, decreased the amplitude and increased the duration of single action potentials. Thus, taken together, these results suggest that the differential sensitivity of outbred lines to the soporific effects of ethanol are paralleled by differences in the sensitivity of Purkinje neurons in vitro to superfusion with ethanol. Because these differences can be observed even when synaptic transmission is largely suppressed, it would appear that these differences are intrinsic to the purkinje neurons themselves.

  6. Mapping the development of cerebellar Purkinje cells in zebrafish.

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    Hamling, Kyla R; Tobias, Zachary J C; Weissman, Tamily A

    2015-11-01

    The cells that comprise the cerebellum perform a complex integration of neural inputs to influence motor control and coordination. The functioning of this circuit depends upon Purkinje cells and other cerebellar neurons forming in the precise place and time during development. Zebrafish provide a useful platform for modeling disease and studying gene function, thus a quantitative metric of normal zebrafish cerebellar development is key for understanding how gene mutations affect the cerebellum. To begin to quantitatively measure cerebellar development in zebrafish, we have characterized the spatial and temporal patterning of Purkinje cells during the first 2 weeks of development. Differentiated Purkinje cells first emerged by 2.8 days post fertilization and were spatially patterned into separate dorsomedial and ventrolateral clusters that merged at around 4 days. Quantification of the Purkinje cell layer revealed that there was a logarithmic increase in both Purkinje cell number as well as overall volume during the first 2 weeks, while the entire region curved forward in an anterior, then ventral direction. Purkinje cell dendrites were positioned next to parallel fibers as early as 3.3 days, and Purkinje cell diameter decreased significantly from 3.3 to 14 days, possibly due to cytoplasmic reappropriation into maturing dendritic arbors. A nearest neighbor analysis showed that Purkinje cells moved slightly apart from each other from 3 to 14 days, perhaps spreading as the organized monolayer forms. This study establishes a quantitative spatiotemporal map of Purkinje cell development in zebrafish that provides an important metric for studies of cerebellar development and disease.

  7. Cell-autonomous death of cerebellar purkinje neurons with autophagy in niemann-pick type C disease.

    Directory of Open Access Journals (Sweden)

    2005-07-01

    Full Text Available Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs. We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.

  8. Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease.

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    Dennis C Ko

    2005-07-01

    Full Text Available Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs. We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.

  9. Long-term potentiation of inhibitory synaptic transmission onto cerebellar Purkinje neurons contributes to adaptation of vestibulo-ocular reflex.

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    Tanaka, Shinsuke; Kawaguchi, Shin-Ya; Shioi, Go; Hirano, Tomoo

    2013-10-23

    Synaptic plasticity in the cerebellum is thought to contribute to motor learning. In particular, long-term depression (LTD) at parallel fiber (PF) to Purkinje neuron (PN) excitatory synapses has attracted much attention of neuroscientists as a primary cellular mechanism for motor learning. In contrast, roles of plasticity at cerebellar inhibitory synapses in vivo remain unknown. Here, we have investigated the roles of long-lasting enhancement of transmission at GABAergic synapses on a PN that is known as rebound potentiation (RP). Previous studies demonstrated that binding of GABAA receptor with GABAA receptor-associated protein (GABARAP) is required for RP, and that a peptide that blocks this binding suppresses RP induction. To address the functional roles of RP, we generated transgenic mice that express this peptide fused to a fluorescent protein selectively in PNs using the PN-specific L7 promoter. These mice failed to show RP, although they showed no changes in the basal amplitude or frequency of miniature IPSCs. The transgenic mice also showed no abnormality in gross cerebellar morphology, LTD, or other excitatory synaptic properties, or intrinsic excitability of PNs. Next, we attempted to evaluate their motor control and learning ability by examining reflex eye movements. The basal dynamic properties of the vestibulo-ocular reflex and optokinetic response, and adaptation of the latter, were normal in the transgenic mice. In contrast, the transgenic mice showed defects in the adaptation of vestibulo-ocular reflex, a model paradigm of cerebellum-dependent motor learning. These results together suggest that RP contributes to a certain type of motor learning.

  10. Signals and Circuits in the Purkinje Neuron

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    Ze'ev R Abrams

    2011-09-01

    Full Text Available Purkinje neurons in the cerebellum have over 100,000 inputs organized in an orthogonal geometry, and a single output channel. As the sole output of the cerebellar cortex layer, their complex firing pattern has been associated with motor control and learning. As such they have been extensively modeled and measured using tools ranging from electrophysiology and neuroanatomy, to dynamic systems and artificial intelligence methods. However, there is an alternative approach to analyze and describe the neuronal output of these cells using concepts from Electrical Engineering, particularly signal processing and digital/analog circuits. By viewing the Purkinje neuron as an unknown circuit to be reverse-engineered, we can use the tools that provide the foundations of today’s integrated circuits and communication systems to analyze the Purkinje system at the circuit level. We use Fourier transforms to analyze and isolate the inherent frequency modes in the Purkinje neuron and define 3 unique frequency ranges associated with the cells’ output. Comparing the Purkinje neuron to a signal generator that can be externally modulated adds an entire level of complexity to the functional role of these neurons both in terms of data analysis and information processing, relying on Fourier analysis methods in place of statistical ones. We also re-describe some of the recent literature in the field, using the nomenclature of signal processing. Furthermore, by comparing the experimental data of the past decade with basic electronic circuitry, we can resolve the outstanding controversy in the field, by recognizing that the Purkinje neuron can act as a multivibrator circuit.

  11. Optogenetics in the cerebellum: Purkinje cell-specific approaches for understanding local cerebellar functions.

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    Tsubota, Tadashi; Ohashi, Yohei; Tamura, Keita

    2013-10-15

    The cerebellum consists of the cerebellar cortex and the cerebellar nuclei. Although the basic neuronal circuitry of the cerebellar cortex is uniform everywhere, anatomical data demonstrate that the input and output relationships of the cortex are spatially segregated between different cortical areas, which suggests that there are functional distinctions between these different areas. Perturbation of cerebellar cortical functions in a spatially restricted fashion is thus essential for investigating the distinctions among different cortical areas. In the cerebellar cortex, Purkinje cells are the sole output neurons that send information to downstream cerebellar and vestibular nuclei. Therefore, selective manipulation of Purkinje cell activities, without disturbing other neuronal types and passing fibers within the cortex, is a direct approach to spatially restrict the effects of perturbations. Although this type of approach has for many years been technically difficult, recent advances in optogenetics now enable selective activation or inhibition of Purkinje cell activities, with high temporal resolution. Here we discuss the effectiveness of using Purkinje cell-specific optogenetic approaches to elucidate the functions of local cerebellar cortex regions. We also discuss what improvements to current methods are necessary for future investigations of cerebellar functions to provide further advances.

  12. Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice

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    Mikiko eKayakabe

    2014-01-01

    Full Text Available γ-Aminobutyric acid (GABA is a major inhibitory neurotransmitter in the adult mammalian central nervous system and plays modulatory roles in neural development. The vesicular GABA transporter (VGAT is an essential molecule for GABAergic neurotransmission due to its role in vesicular GABA release. Cerebellar Purkinje cells (PCs are GABAergic projection neurons that are indispensable for cerebellar function. To elucidate the significance of VGAT in cerebellar PCs, we generated and characterized PC-specific VGAT knockout (L7-VGAT mice. VGAT mRNAs and proteins were specifically absent in the 40-week-old L7-VGAT PCs. The morphological charactereistics, such as lamination and foliation of the cerebellar cortex, of the L7-VGAT mice were similar to those of the control littermate mice. Moreover, the protein expression levels and patterns of pre- (calbindin and parvalbumin and postsynaptic (GABA-A receptor α1 subunit (GABAARα1 and gephyrin molecules between the L7-VGAT and control mice were similar in the deep cerebellar nuclei that receive PC projections. However, the L7-VGAT mice performed poorly in the accelerating rotarod test and displayed ataxic gait in the footprint test. The L7-VGAT mice also exhibited severer ataxia as VGAT deficits progressed. These results suggest that VGAT in cerebellar Purkinje cells is not essential for the rough maintenance of cerebellar structure, but does play an important role in motor coordination. The L7-VGAT mice are a novel model of ataxia without PC degeneration, and would also be useful for studying the role of Purkinje cells in cognition and emotion.

  13. Molecular markers of neuronal progenitors in the embryonic cerebellar anlage.

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    Morales, Daniver; Hatten, Mary E

    2006-11-22

    The cerebellum, like the cerebrum, includes a nuclear structure and an overlying cortical structure. Experiments in the past decade have expanded knowledge beyond the traditional function of the cerebellum to include critical roles in motor learning and memory and sensory discrimination. The initial steps in cerebellar development depend on inductive signaling involving FGF and Wnt proteins produced at the mesencephalic/metencephalic boundary. To address the issue of how individual cerebellar cell fates within the cerebellar territory are specified, we examined the expression of transcription factors, including mammalian homologues of LIM homeodomain-containing proteins, basic helix-loop-helix proteins, and three amino acid loop-containing proteins. The results of these studies show that combinatorial codes of transcription factors define precursors of the cerebellar nuclei, and both Purkinje cells and granule neurons of the cerebellar cortex. Examination of gene expression patterns in several hundred lines of Egfp-BAC (bacterial artificial chromosome) transgenic mice in the GENSAT Project revealed numerous genes with restricted expression in cerebellar progenitor populations, including genes specific for cerebellar nuclear precursors and Purkinje cell precursors. In addition, we identified patterns of gene expression that link granule and Purkinje cells to their precerebellar nuclei. These results identify molecular pathways that offer new insights on the development of the nuclear and cortical structures of the cerebellum, as well as components of the cerebellar circuitry.

  14. Purkinje cell-specific ablation of Cav2.1 channels is sufficient to cause cerebellar ataxia in mice.

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    Todorov, Boyan; Kros, Lieke; Shyti, Reinald; Plak, Petra; Haasdijk, Elize D; Raike, Robert S; Frants, Rune R; Hess, Ellen J; Hoebeek, Freek E; De Zeeuw, Chris I; van den Maagdenberg, Arn M J M

    2012-03-01

    The Cacna1a gene encodes the α(1A) subunit of voltage-gated Ca(V)2.1 Ca(2+) channels that are involved in neurotransmission at central synapses. Ca(V)2.1-α(1)-knockout (α1KO) mice, which lack Ca(V)2.1 channels in all neurons, have a very severe phenotype of cerebellar ataxia and dystonia, and usually die around postnatal day 20. This early lethality, combined with the wide expression of Ca(V)2.1 channels throughout the cerebellar cortex and nuclei, prohibited determination of the contribution of particular cerebellar cell types to the development of the severe neurobiological phenotype in Cacna1a mutant mice. Here, we crossed conditional Cacna1a mice with transgenic mice expressing Cre recombinase, driven by the Purkinje cell-specific Pcp2 promoter, to specifically ablate the Ca(V)2.1-α(1A) subunit and thereby Ca(V)2.1 channels in Purkinje cells. Purkinje cell Ca(V)2.1-α(1A)-knockout (PCα1KO) mice aged without difficulties, rescuing the lethal phenotype seen in α1KO mice. PCα1KO mice exhibited cerebellar ataxia starting around P12, much earlier than the first signs of progressive Purkinje cell loss, which appears in these mice between P30 and P45. Secondary cell loss was observed in the granular and molecular layers of the cerebellum and the volume of all individual cerebellar nuclei was reduced. In this mouse model with a cell type-specific ablation of Ca(V)2.1 channels, we show that ablation of Ca(V)2.1 channels restricted to Purkinje cells is sufficient to cause cerebellar ataxia. We demonstrate that spatial ablation of Ca(V)2.1 channels may help in unraveling mechanisms of human disease.

  15. Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development

    International Nuclear Information System (INIS)

    Oligodendrocytes (OLs) are the glial cells of the central nervous system (CNS) classically known to be devoted to the formation of myelin sheaths around most axons of the vertebrate brain. We have addressed the role of these cells during cerebellar development, by ablating OLs in vivo. Previous analyses had indicated that OL ablation during the first six postnatal days results into a striking cerebellar phenotype, whose major features are a strong reduction of granule neurons and aberrant Purkinje cells development. These two cell types are highly interconnected during cerebellar development through the production of molecules that help their proliferation, differentiation and maintenance. In this article, we present data showing that OL ablation has major effects on the physiology of Purkinje (PC) and granule cells (GC). In particular, OL ablation results into a reduction of sonic hedgehog (Shh), Brain Derived Neurotrophic Factor (BDNF), and Reelin (Rln) expression. These results indicate that absence of OLs profoundly alters the normal cerebellar developmental program

  16. Multiple types of cerebellar target neurons and their circuitry in the vestibulo-ocular reflex.

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    Shin, Minyoung; Moghadam, Setareh H; Sekirnjak, Chris; Bagnall, Martha W; Kolkman, Kristine E; Jacobs, Richard; Faulstich, Michael; du Lac, Sascha

    2011-07-27

    The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles. Using a combination of anatomical tracing and electrophysiological recordings in transgenic mouse lines, we identified several classes of neurons in the medial vestibular nucleus that receive Purkinje cell synapses from the cerebellar flocculus. Glycinergic and glutamatergic flocculus target neurons (FTNs) with somata densely surrounded by Purkinje cell terminals projected axons to the ipsilateral abducens and oculomotor nuclei, respectively. Of three additional types of FTNs that were sparsely innervated by Purkinje cells, glutamatergic and glycinergic neurons projected to the contralateral and ipsilateral abducens, respectively, and GABAergic neurons projected to contralateral vestibular nuclei. Densely innervated FTNs had high spontaneous firing rates and pronounced postinhibitory rebound firing, and were physiologically homogeneous, whereas the intrinsic excitability of sparsely innervated FTNs varied widely. Heterogeneity in the molecular expression, physiological properties, and postsynaptic targets of FTNs implies that Purkinje cell activity influences the neural control of eye movements in several distinct ways. These results indicate that the cerebellum regulates a simple reflex behavior via at least five different cell types that are postsynaptic to Purkinje cells.

  17. A spiking network model of cerebellar Purkinje cells and molecular layer interneurons exhibiting irregular firing

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    William eLennon

    2014-12-01

    Full Text Available While the anatomy of the cerebellar microcircuit is well studied, how it implements cerebellar function is not understood. A number of models have been proposed to describe this mechanism but few emphasize the role of the vast network Purkinje cells (PKJs form with the molecular layer interneurons (MLIs – the stellate and basket cells. We propose a model of the MLI-PKJ network composed of simple spiking neurons incorporating the major anatomical and physiological features. In computer simulations, the model reproduces the irregular firing patterns observed in PKJs and MLIs in vitro and a shift toward faster, more regular firing patterns when inhibitory synaptic currents are blocked. In the model, the time between PKJ spikes is shown to be proportional to the amount of feedforward inhibition from an MLI on average. The two key elements of the model are: (1 spontaneously active PKJs and MLIs due to an endogenous depolarizing current, and (2 adherence to known anatomical connectivity along a parasagittal strip of cerebellar cortex. We propose this model to extend previous spiking network models of the cerebellum and for further computational investigation into the role of irregular firing and MLIs in cerebellar learning and function.

  18. Cultures of Cerebellar Granule Neurons

    OpenAIRE

    sprotocols

    2014-01-01

    Authors: Parizad M. Bilimoria and Azad Bonni1 Corresponding author ([]()) ### INTRODUCTION Primary cultures of granule neurons from the post-natal rat cerebellum provide an excellent model system for molecular and cell biological studies of neuronal development and function. The cerebellar cortex, with its highly organized structure and few neuronal subtypes, offers a well-characterized neural circuitry. Many fundamental insight...

  19. STD-dependent and independent encoding of input irregularity as spike rate in a computational model of a cerebellar nucleus neuron

    NARCIS (Netherlands)

    J. Luthman (Johannes); F.E. Hoebeek (Freek); R. Maex (Reinoud); N. Davey (Neil); R. Adams (Rod); C.I. de Zeeuw (Chris); V. Steuber (Volker)

    2011-01-01

    textabstractNeurons in the cerebellar nuclei (CN) receive inhibitory inputs from Purkinje cells in the cerebellar cortex and provide the major output from the cerebellum, but their computational function is not well understood. It has recently been shown that the spike activity of Purkinje cells is

  20. A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation.

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    Lihong Zhao

    2011-05-01

    Full Text Available Sphingolipids, lipids with a common sphingoid base (also termed long chain base backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln and toppler (to, with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydroceramide synthase 1 (CerS1, which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

  1. Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1α

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    Elizabeth K Lucas

    2015-01-01

    Full Text Available Alterations in the expression and activity of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (ppargc1a or PGC-1α have been reported in multiple movement disorders, yet it is unclear how a lack of PGC-1α impacts transcription and function of the cerebellum, a region with high PGC-1α expression. We show here that mice lacking PGC-1α exhibit ataxia in addition to the previously described deficits in motor coordination. Using q-RT-PCR in cerebellar homogenates from PGC-1α -/- mice, we measured expression of 37 microarray-identified transcripts upregulated by PGC-1α in SH-SY5Y neuroblastoma cells with neuroanatomical overlap with PGC-1α or parvalbumin (PV, a calcium buffer highly expressed by Purkinje cells. We found significant reductions in transcripts with synaptic (complexin1, Cplx1; Pacsin2, structural (neurofilament heavy chain, Nefh, and metabolic (isocitrate dehydrogenase 3a, Idh3a; neutral cholesterol ester hydrolase 1, Nceh1; pyruvate dehydrogenase alpha 1, Pdha1; phytanoyl-CoA hydroxylase, Phyh; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, Uqcrfs1 functions. Using conditional deletion of PGC-1α in PV-positive neurons, we determined that 50% of PGC-1α expression and a reduction in a subset of these transcripts could be explained by its concentration in PV-positive neuronal populations in the cerbellum. To determine whether there were functional consequences associated with these changes, we conducted stereological counts and spike rate analysis in Purkinje cells, a cell type rich in PV, from PGC-1α -/- mice. We observed a significant loss of Purkinje cells by six weeks of age, and the remaining Purkinje cells exhibited a 50% reduction in spike rate. Together, these data highlight the complexity of PGC-1α’s actions in the central nervous system and suggest that dysfunction in multiple cell types contribute to motor deficits in the context of PGC-1α deficiency.

  2. Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1α

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    Lucas, Elizabeth K.; Reid, Courtney S.; McMeekin, Laura J.; Dougherty, Sarah E.; Floyd, Candace L.; Cowell, Rita M.

    2014-01-01

    Alterations in the expression and activity of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (ppargc1a or PGC-1α) have been reported in multiple movement disorders, yet it is unclear how a lack of PGC-1α impacts transcription and function of the cerebellum, a region with high PGC-1α expression. We show here that mice lacking PGC-1α exhibit ataxia in addition to the previously described deficits in motor coordination. Using q-RT-PCR in cerebellar homogenates from PGC-1α−/− mice, we measured expression of 37 microarray-identified transcripts upregulated by PGC-1α in SH-SY5Y neuroblastoma cells with neuroanatomical overlap with PGC-1α or parvalbumin (PV), a calcium buffer highly expressed by Purkinje cells. We found significant reductions in transcripts with synaptic (complexin1, Cplx1; Pacsin2), structural (neurofilament heavy chain, Nefh), and metabolic (isocitrate dehydrogenase 3a, Idh3a; neutral cholesterol ester hydrolase 1, Nceh1; pyruvate dehydrogenase alpha 1, Pdha1; phytanoyl-CoA hydroxylase, Phyh; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, Uqcrfs1) functions. Using conditional deletion of PGC-1α in PV-positive neurons, we determined that 50% of PGC-1α expression and a reduction in a subset of these transcripts could be explained by its concentration in PV-positive neuronal populations in the cerbellum. To determine whether there were functional consequences associated with these changes, we conducted stereological counts and spike rate analysis in Purkinje cells, a cell type rich in PV, from PGC-1α−/− mice. We observed a significant loss of Purkinje cells by 6 weeks of age, and the remaining Purkinje cells exhibited a 50% reduction in spike rate. Together, these data highlight the complexity of PGC-1α's actions in the central nervous system and suggest that dysfunction in multiple cell types contribute to motor deficits in the context of PGC-1α deficiency. PMID

  3. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells

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    Ma Wei-Hsien

    2011-08-01

    Full Text Available Abstract Background Spinocerebellar ataxia (SCA refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model. Method Transgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain. Results Intravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice. Conclusion Intravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor

  4. Fear conditioning-related changes in cerebellar Purkinje cell activities in goldfish

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    Yoshida Masayuki

    2012-10-01

    Full Text Available Abstract Background Fear conditioning-induced changes in cerebellar Purkinje cell responses to a conditioned stimulus have been reported in rabbits. It has been suggested that synaptic long-term potentiation and the resulting increases in firing rates of Purkinje cells are related to the acquisition of conditioned fear in mammals. However, Purkinje cell activities during acquisition of conditioned fear have not been analysed, and changes in Purkinje cell activities throughout the development of conditioned fear have not yet been investigated. In the present study, we tracked Purkinje cell activities throughout a fear conditioning procedure and aimed to elucidate further how cerebellar circuits function during the acquisition and expression of conditioned fear. Methods Activities of single Purkinje cells in the corpus cerebelli were tracked throughout a classical fear conditioning procedure in goldfish. A delayed conditioning paradigm was used with cardiac deceleration as the conditioned response. Conditioning-related changes of Purkinje cell responses to a conditioned stimulus and unconditioned stimulus were examined. Results The majority of Purkinje cells sampled responded to the conditioned stimulus by either increasing or decreasing their firing rates before training. Although there were various types of conditioning-related changes in Purkinje cells, more than half of the cells showed suppressed activities in response to the conditioned stimulus after acquisition of conditioned fear. Purkinje cells that showed unconditioned stimulus-coupled complex-spike firings also exhibited conditioning-related suppression of simple-spike responses to the conditioned stimulus. A small number of Purkinje cells showed increased excitatory responses in the acquisition sessions. We found that the magnitudes of changes in the firing frequencies of some Purkinje cells in response to the conditioned stimulus correlated with the magnitudes of the conditioned

  5. Coexistence of dopamine-beta-hydroxylase and activated protein-2 alpha in rat cerebellar Purkinje cells

    Institute of Scientific and Technical Information of China (English)

    Kejian Wang; Wei Li; Shanquan Sun; Zhongqin Ren; Guiqiong He

    2009-01-01

    BACKGROUND:Tyrosine hydroxylase and phenylethanolamine-n-methyl transferase expression coexist in Purkinje cells of the rat cerebellum.Numerous reports have also been published addressing whether dopamine-beta-hydroxylase (DBH) expression exists in cerebellar Purkinje cells.OBJECTIVE:To investigate the coexistence of DBH and activator protein-2α expression in rat cerebellar Purkinje cells.DESIGN,TIME AND SETTING:A cell morphological study was performed at the Institute of Neuroscience,Chongqing Medical University,China in May 2007.MATERIALS:Ten healthy Wistar rats,of either gender,aged 14 weeks,served as experimental animals.Rabbit anti-mouse DBH,goat anti-mouse activator protein-2α and rabbit anti-mouse β-actin (Santa Cruz Biotechnology,Inc.,USA),horseradish peroxidase-labeled goat anti-rabbit IgG,FITC-labeled mouse anti-rabbit IgG,and Cy3-labeled mouse anti-goat IgG (Boster,Wuhan,China),were used in this study.METHODS:Immunohistochemical staining was used to measure the expression of DBH or activator protein-2α,with double-label immunofluorescence being employed to determine coexpression of both,in the cerebellum of 5 randomly selected rats.Western blot assay was utilized to determine the expression of DBH and activator protein-2α in the cerebellum of the remaining 5 rats.MAIN OUTCOME MEASURES:Expression,localization and coexistence of DBH and activator protein-2α in the cerebellum were measured separately.RESULTS:Immunohistochemical staining demonstrated that cerebellar Purkinje cells stained positive for DBH and activator protein-2α.Western blot assay also demonstrated DBH and activator protein-2α expression in the cerebellum.Double-labeling immunofluorescence showed the coexistence of DBH and activator protein-2α in cerebellar Purkinje cells.CONCLUSION:Norepinephrine and activator protein-2α coexist in rat cerebellar Purkinje cells.

  6. Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells.

    OpenAIRE

    Konnerth, A.; Dreessen, J; Augustine, G J

    1992-01-01

    We have performed experiments designed to test the hypothesis that long-term depression (LTD) of excitatory synaptic transmission in the cerebellar cortex is caused by a rise in postsynaptic Ca concentration. These experiments combined measurements of synaptic efficacy, performed with the thin slice patch clamp technique, with fura-2 measurements of intracellular Ca concentration ([Ca]i) in single cerebellar Purkinje cells. Simultaneous activation of the climbing fiber and parallel fibers inn...

  7. Role of synchronous activation of cerebellar purkinje cell ensembles in multi-joint movement control

    NARCIS (Netherlands)

    T.M. Hoogland (Tycho); J.R. de Gruijl (Jornt); L. Witter (Laurens); M.I. Canto (Marcia Irene); C.I. de Zeeuw (Chris)

    2015-01-01

    textabstractIt is a longstanding question in neuroscience how elaborate multi-joint movements are coordinated coherently. Microzones of cerebellar Purkinje cells (PCs) are thought to mediate this coordination by controlling the timing of particular motor domains. However, it remains to be elucidated

  8. Role of Synchronous Activation of Cerebellar Purkinje Cell Ensembles in Multi-joint Movement Control

    NARCIS (Netherlands)

    Hoogland, Tycho M; De Gruijl, Jornt R; Witter, Laurens; Canto, Cathrin B; De Zeeuw, Chris I

    2015-01-01

    It is a longstanding question in neuroscience how elaborate multi-joint movements are coordinated coherently. Microzones of cerebellar Purkinje cells (PCs) are thought to mediate this coordination by controlling the timing of particular motor domains. However, it remains to be elucidated to what ext

  9. Ectopic cerebellar cell migration causes maldevelopment of Purkinje cells and abnormal motor behaviour in Cxcr4 null mice.

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    Guo-Jen Huang

    Full Text Available SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice.

  10. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD

    OpenAIRE

    He, Qionger; Titley, Heather; Grasselli, Giorgio; Piochon, Claire; Hansel, Christian

    2012-01-01

    Ethanol profoundly influences cerebellar circuit function and motor control. It has recently been demonstrated that functional N-methyl-d-aspartate (NMDA) receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in the adult cerebellum. Using whole cell patch-clamp recordings from mouse cerebellar slices, we examined whether ethanol can affect NMDA receptor signaling in mature Purkinje cells. NMDA receptor-mediated currents were isolated by bath application of...

  11. Alcohol impairs long-term depression at the cerebellar parallel fiber-Purkinje cell synapse

    OpenAIRE

    Belmeguenai, A.; Botta, Paolo; Weber, John; Carta, Mario; De Ruiter, Martijn; De Zeeuw, Chris; Valenzuela, Fernando; Hansel, Christian

    2008-01-01

    textabstractAcute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects...

  12. Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency.

    Science.gov (United States)

    De Munter, Stephanie; Verheijden, Simon; Vanderstuyft, Esther; Malheiro, Ana Rita; Brites, Pedro; Gall, David; Schiffmann, Serge N; Baes, Myriam

    2016-10-01

    The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved. Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4weeks, Nestin-Mfp2(-/-) mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells. PMID:27353294

  13. Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning

    NARCIS (Netherlands)

    M. Schonewille (Martijn); A. Belmeguenai; S.K.E. Koekkoek (Bas); S.H. Houtman (Simone Hendrika); H.J. Boele (Henk-Jan); B.J. van Beugen (Boeke); Z. Gao (Zhenyu); A.M. Badura (Aleksandra); G. Ohtsuki (Gen); W.E. Amerika; E. Hosy; F.E. Hoebeek (Freek); Y. Elgersma (Ype); C.R.W. Hansel (Christian); C.I. de Zeeuw (Chris)

    2010-01-01

    textabstractCerebellar motor learning is required to obtain procedural skills. Studies have provided supportive evidence for a potential role of kinase-mediated long-term depression (LTD) at the parallel fiber to Purkinje cell synapse in cerebellar learning. Recently, phosphatases have been implicat

  14. Alternative splicing generates a smaller assortment of CaV2.1 transcripts in cerebellar Purkinje cells than in the cerebellum.

    Science.gov (United States)

    Kanumilli, Srinivasan; Tringham, Elizabeth W; Payne, C Elizabeth; Dupere, Jonathan R B; Venkateswarlu, Kanamarlapudi; Usowicz, Maria M

    2006-01-12

    P/Q-type calcium channels control many calcium-driven functions in the brain. The CACNA1A gene encoding the pore-forming CaV2.1 (alpha1A) subunit of P/Q-type channels undergoes alternative splicing at multiple loci. This results in channel variants with different phenotypes. However, the combinatorial patterns of alternative splice events at two or more loci, and hence the diversity of CaV2.1 transcripts, are incompletely defined for specific brain regions and types of brain neurons. Using RT-PCR and splice variant-specific primers, we have identified multiple CaV2.1 transcript variants defined by different pairs of splice events in the cerebellum of adult rat. We have uncovered new splice variations between exons 28 and 34 (some of which predict a premature stop codon) and a new variation in exon 47 (which predicts a novel extended COOH-terminus). Single cell RT-PCR reveals that each individual cerebellar Purkinje neuron also expresses multiple alternative CaV2.1 transcripts, but the assortment is smaller than in the cerebellum. Two of these variants encode different extended COOH-termini which are not the same as those previously reported in Purkinje cells of the mouse. Our patch-clamp recordings show that calcium channel currents in the soma and dendrites of Purkinje cells are largely inhibited by a concentration of omega-agatoxin IVA selective for P-type over Q-type channels, suggesting that the different transcripts may form phenotypic variants of P-type calcium channels in Purkinje cells. These results expand the known diversity of CaV2.1 transcripts in cerebellar Purkinje cells, and propose the selective expression of distinct assortments of CaV2.1 transcripts in different brain neurons and species.

  15. Regulation and functional roles of rebound potentiation at cerebellar stellate cell - Purkinje cell synapses

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    Tomoo eHirano

    2014-02-01

    Full Text Available Purkinje cells receive both excitatory and inhibitory synaptic inputs and send sole output from the cerebellar cortex. Long-term depression, a type of synaptic plasticity, at excitatory parallel fiber–Purkinje cell synapses has been studied extensively as a primary cellular mechanism of motor learning. On the other hand, at inhibitory synapses on a Purkinje cell, postsynaptic depolarization induces long-lasting potentiation of GABAergic synaptic transmission. This synaptic plasticity is called rebound potentiation (RP, and its molecular regulatory mechanisms have been studied. The increase in intracellular Ca2+ concentration caused by depolarization induces RP through enhancement of GABAA receptor (GABAAR responsiveness. RP induction depends on binding of GABAAR with GABAAR associated protein (GABARAP which is regulated by Ca2+/calmodulin-dependent kinase II (CaMKII. Whether RP is induced or not is determined by the balance between phosphorylation and de-phosphorylation activities regulated by intracellular Ca2+ and by metabotropic GABA and glutamate receptors. Recent studies have revealed that the subunit composition of CaMKII has significant impact on RP induction. A Purkinje cell expresses both alpha- and beta-CaMKII, and the latter has much higher affinity for Ca2+/calmodulin than the former. It was shown that when the relative amount of alpha- to beta-CaMKII is large, RP induction is suppressed. The functional significance of RP has also been studied using transgenic mice in which a peptide inhibiting association of GABARAP and GABAAR is expressed selectively in Purkinje cells. The transgenic mice show abrogation of RP and subnormal adaptation of vestibulo-ocular reflex, a type of motor learning. Thus, RP is involved in a certain type of motor learning.

  16. A new Purkinje cell antibody (anti-Ca associated with subacute cerebellar ataxia: immunological characterization

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    Horn Sigrun

    2010-03-01

    Full Text Available Abstract We report on a newly discovered serum and cerebrospinal fluid (CSF reactivity to Purkinje cells (PCs associated with subacute inflammatory cerebellar ataxia. The patient, a previously healthy 33-year-old lady, presented with severe limb and gait ataxia, dysarthria, and diplopia two weeks after she had recovered from a common cold. Immunohistochemical studies on mouse, rat, and monkey brain sections revealed binding of a high-titer (up to 1:10,000 IgG antibody to the cerebellar molecular layer, Purkinje cell (PC layer, and white matter. The antibody is highly specific for PCs and binds to the cytoplasm as well as to the inner side of the membrane of PC somata, dendrites and axons. It is produced by B cell clones within the CNS, belongs to the IgG1 subclass, and activates complement in vitro. Western blotting of primate cerebellum extract revealed binding of CSF and serum IgG to an 80-97 kDa protein. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic antibodies known to be associated with cerebellar ataxia. Screening of >9000 human full length proteins by means of a protein array and additional confirmatory experiments revealed Rho GTPase activating protein 26 (ARHGAP26, GRAF, oligophrenin-1-like protein as the target antigen. Preadsorption of the patient's serum with human ARHGAP26 but not preadsorption with other proteins resulted in complete loss of PC staining. Our findings suggest a role of autoimmunity against ARHGAP26 in the pathogenesis of subacute inflammatory cerebellar ataxia, and extend the panel of diagnostic markers for this devastating disease.

  17. STD-dependent and independent encoding of input irregularity as spike rate in a computational model of a cerebellar nucleus neuron.

    Science.gov (United States)

    Luthman, Johannes; Hoebeek, Freek E; Maex, Reinoud; Davey, Neil; Adams, Rod; De Zeeuw, Chris I; Steuber, Volker

    2011-12-01

    Neurons in the cerebellar nuclei (CN) receive inhibitory inputs from Purkinje cells in the cerebellar cortex and provide the major output from the cerebellum, but their computational function is not well understood. It has recently been shown that the spike activity of Purkinje cells is more regular than previously assumed and that this regularity can affect motor behaviour. We use a conductance-based model of a CN neuron to study the effect of the regularity of Purkinje cell spiking on CN neuron activity. We find that increasing the irregularity of Purkinje cell activity accelerates the CN neuron spike rate and that the mechanism of this recoding of input irregularity as output spike rate depends on the number of Purkinje cells converging onto a CN neuron. For high convergence ratios, the irregularity induced spike rate acceleration depends on short-term depression (STD) at the Purkinje cell synapses. At low convergence ratios, or for synchronised Purkinje cell input, the firing rate increase is independent of STD. The transformation of input irregularity into output spike rate occurs in response to artificial input spike trains as well as to spike trains recorded from Purkinje cells in tottering mice, which show highly irregular spiking patterns. Our results suggest that STD may contribute to the accelerated CN spike rate in tottering mice and they raise the possibility that the deficits in motor control in these mutants partly result as a pathological consequence of this natural form of plasticity.

  18. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice

    Science.gov (United States)

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  19. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice.

    Science.gov (United States)

    Peter, Saša; Ten Brinke, Michiel M; Stedehouder, Jeffrey; Reinelt, Claudia M; Wu, Bin; Zhou, Haibo; Zhou, Kuikui; Boele, Henk-Jan; Kushner, Steven A; Lee, Min Goo; Schmeisser, Michael J; Boeckers, Tobias M; Schonewille, Martijn; Hoebeek, Freek E; De Zeeuw, Chris I

    2016-01-01

    Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD. PMID:27581745

  20. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice.

    Science.gov (United States)

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  1. Properties of bilateral spinocerebellar activation of cerebellar cortical neurons

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    Pontus eGeborek

    2014-10-01

    Full Text Available We aimed to explore the cerebellar cortical inputs from two spinocerebellar pathways, the spinal border cell-component of the ventral spinocerebellar tract (SBC-VSCT and the dorsal spinocerebellar tract (DSCT, respectively, in the sublobule C1 of the cerebellar posterior lobe. The two pathways were activated by electrical stimulation of the contralateral lateral funiculus (coLF and the ipsilateral LF (iLF at lower thoracic levels. Most granule cells in sublobule C1 did not respond at all but part of the granule cell population displayed high-intensity responses to either coLF or iLF stimulation. As a rule, Golgi cells and Purkinje cell simple spikes responded to input from both LFs, although Golgi cells could be more selective. In addition, a small population of granule cells responded to input from both the coLF and the iLF. However, in these cases, similarities in the temporal topography and magnitude of the responses suggested that the same axons were stimulated from the two LFs, i.e. that the axons of individual spinocerebellar neurons could be present in both funiculi. This was also confirmed for a population of spinal neurons located within known locations of SBC-VSCT neurons and dorsal horn DSCT neurons. We conclude that bilateral spinocerebellar responses can occur in cerebellar granule cells, but the VSCT and DSCT systems that provide the input can also be organized bilaterally. The implications for the traditional functional separation of VSCT and DSCT systems and the issue whether granule cells primarily integrate functionally similar information or not are discussed.

  2. Probabilistic identification of cerebellar cortical neurones across species.

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    Gert Van Dijck

    Full Text Available Despite our fine-grain anatomical knowledge of the cerebellar cortex, electrophysiological studies of circuit information processing over the last fifty years have been hampered by the difficulty of reliably assigning signals to identified cell types. We approached this problem by assessing the spontaneous activity signatures of identified cerebellar cortical neurones. A range of statistics describing firing frequency and irregularity were then used, individually and in combination, to build Gaussian Process Classifiers (GPC leading to a probabilistic classification of each neurone type and the computation of equi-probable decision boundaries between cell classes. Firing frequency statistics were useful for separating Purkinje cells from granular layer units, whilst firing irregularity measures proved most useful for distinguishing cells within granular layer cell classes. Considered as single statistics, we achieved classification accuracies of 72.5% and 92.7% for granular layer and molecular layer units respectively. Combining statistics to form twin-variate GPC models substantially improved classification accuracies with the combination of mean spike frequency and log-interval entropy offering classification accuracies of 92.7% and 99.2% for our molecular and granular layer models, respectively. A cross-species comparison was performed, using data drawn from anaesthetised mice and decerebrate cats, where our models offered 80% and 100% classification accuracy. We then used our models to assess non-identified data from awake monkeys and rabbits in order to highlight subsets of neurones with the greatest degree of similarity to identified cell classes. In this way, our GPC-based approach for tentatively identifying neurones from their spontaneous activity signatures, in the absence of an established ground-truth, nonetheless affords the experimenter a statistically robust means of grouping cells with properties matching known cell classes. Our

  3. Persistent posttetanic depression at cerebellar parallel fiber to Purkinje cell synapses.

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    Astrid Bergerot

    Full Text Available Plasticity at the cerebellar parallel fiber to Purkinje cell synapse may underlie information processing and motor learning. In vivo, parallel fibers appear to fire in short high frequency bursts likely to activate sparsely distributed synapses over the Purkinje cell dendritic tree. Here, we report that short parallel fiber tetanic stimulation evokes a ∼7-15% depression which develops over 2 min and lasts for at least 20 min. In contrast to the concomitantly evoked short-term endocannabinoid-mediated depression, this persistent posttetanic depression (PTD does not exhibit a dependency on the spatial pattern of synapse activation and is not caused by any detectable change in presynaptic calcium signaling. This persistent PTD is however associated with increased paired-pulse facilitation and coefficient of variation of synaptic responses, suggesting that its expression is presynaptic. The chelation of postsynaptic calcium prevents its induction, suggesting that post- to presynaptic (retrograde signaling is required. We rule out endocannabinoid signaling since the inhibition of type 1 cannabinoid receptors, monoacylglycerol lipase or vanilloid receptor 1, or incubation with anandamide had no detectable effect. The persistent PTD is maximal in pre-adolescent mice, abolished by adrenergic and dopaminergic receptors block, but unaffected by adrenergic and dopaminergic agonists. Our data unveils a novel form of plasticity at parallel fiber synapses: a persistent PTD induced by physiologically relevant input patterns, age-dependent, and strongly modulated by the monoaminergic system. We further provide evidence supporting that the plasticity mechanism involves retrograde signaling and presynaptic diacylglycerol.

  4. Adaptive control of 2-wheeled balancing robot by cerebellar neuronal network model.

    Science.gov (United States)

    Tanaka, Yoshiyuki; Ohata, Yohei; Kawamoto, Tomohiro; Hirata, Yutaka

    2010-01-01

    A new adaptive motor controller was constructed, and tested on the control of a 2-wheeled balancing robot in simulation and real world. The controller consists of a feedback (PD) controller and a cerebellar neuronal network model. The structure of the cerebellar model was configured based upon known anatomical neuronal connection in the cerebellar cortex. Namely it consists of 120 granular (Gr) cells, 1 Golgi cell, 6 basket/stellate cells, and 1 Purkinje (Pk) cell. Each cell is described by a typical artificial neuron model that outputs a weighted sum of inputs after a sigmoidal nonlinear transformation. The 2 components of the proposed controller work in parallel, in a way that the cerebellar model adaptively modifies the synaptic weights between Gr and Pk as in the real cerebellum to minimize the output of the PD controller. We demonstrate that the proposed controller successfully controls a 2-wheeled balancing robot, and the cerebellar model rapidly takes over the PD controller in simulation. We also show that an abrupt load change on the robot, which the PD controller alone cannot compensate for, can be adaptively compensated by the cerebellar model. We further confirmed that the proposed controller can be applied to the control of the robot in real world.

  5. In vivo analysis of inhibitory synaptic inputs and rebounds in deep cerebellar nuclear neurons.

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    Fredrik Bengtsson

    Full Text Available Neuronal function depends on the properties of the synaptic inputs the neuron receive and on its intrinsic responsive properties. However, the conditions for synaptic integration and activation of intrinsic responses may to a large extent depend on the level of background synaptic input. In this respect, the deep cerebellar nuclear (DCN neurons are of particular interest: they feature a massive background synaptic input and an intrinsic, postinhibitory rebound depolarization with profound effects on the synaptic integration. Using in vivo whole cell patch clamp recordings from DCN cells in the cat, we find that the background of Purkinje cell input provides a tonic inhibitory synaptic noise in the DCN cell. Under these conditions, individual Purkinje cells appear to have a near negligible influence on the DCN cell and clear-cut rebounds are difficult to induce. Peripheral input that drives the simple spike output of the afferent PCs to the DCN cell generates a relatively strong DCN cell inhibition, but do not induce rebounds. In contrast, synchronized climbing fiber activation, which leads to a synchronized input from a large number of Purkinje cells, can induce profound rebound responses. In light of what is known about climbing fiber activation under behaviour, the present findings suggest that DCN cell rebound responses may be an unusual event. Our results also suggest that cortical modulation of DCN cell output require a substantial co-modulation of a large proportion of the PCs that innervate the cell, which is a possible rationale for the existence of the cerebellar microcomplex.

  6. GlyT2+ Neurons in the Lateral Cerebellar Nucleus

    OpenAIRE

    Uusisaari, Marylka; Knöpfel, Thomas

    2009-01-01

    The deep cerebellar nuclei (DCN) are a major hub in the cerebellar circuitry but the functional classification of their neurons is incomplete. We have previously characterized three cell groups in the lateral cerebellar nucleus: large non-GABAergic neurons and two groups of smaller neurons, one of which express green fluorescence protein (GFP) in a GAD67/GFP mouse line and is therefore GABAergic. However, as a substantial number of glycinergic and glycine/GABA co-expressing neurons have been ...

  7. Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.

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    Constantin Yanicostas

    Full Text Available The expansion of a polyglutamine (polyQ tract in the N-terminal region of ataxin-7 (atxn7 is the causative event in spinocerebellar ataxia type 7 (SCA7, an autosomal dominant neurodegenerative disorder mainly characterized by progressive, selective loss of rod-cone photoreceptors and cerebellar Purkinje and granule cells. The molecular and cellular processes underlying this restricted neuronal vulnerability, which contrasts with the broad expression pattern of atxn7, remains one of the most enigmatic features of SCA7, and more generally of all polyQ disorders. To gain insight into this specific neuronal vulnerability and achieve a better understanding of atxn7 function, we carried out a functional analysis of this protein in the teleost fish Danio rerio. We characterized the zebrafish atxn7 gene and its transcription pattern, and by making use of morpholino-oligonucleotide-mediated gene inactivation, we analysed the phenotypes induced following mild or severe zebrafish atxn7 depletion. Severe or nearly complete zebrafish atxn7 loss-of-function markedly impaired embryonic development, leading to both early embryonic lethality and severely deformed embryos. More importantly, in relation to SCA7, moderate depletion of the protein specifically, albeit partially, prevented the differentiation of both retina photoreceptors and cerebellar Purkinje and granule cells. In addition, [1-232] human atxn7 fragment rescued these phenotypes showing strong function conservation of this protein through evolution. The specific requirement for zebrafish atxn7 in the proper differentiation of cerebellar neurons provides, to our knowledge, the first in vivo evidence of a direct functional relationship between atxn7 and the differentiation of Purkinje and granule cells, the most crucial neurons affected in SCA7 and most other polyQ-mediated SCAs. These findings further suggest that altered protein function may play a role in the pathophysiology of the disease, an

  8. Preferential Transport and Metabolism of Glucose in Bergmann Glia over Purkinje Cells: A Multiphoton Study of Cerebellar Slices

    Institute of Scientific and Technical Information of China (English)

    L.F.BARROS; R.COURJARET; P.JAKOBY; A.LOAIZA; C.LOHR; J.W.DEITMER

    2009-01-01

    horizontally across the molecular layer, presumably through gap junctions between Bergmann glial cells. Our main conclusion is that in acute cerebellar slices, the glucose transport capacity and glycolytic rate of Bergmann glia are several-fold higher than those of Purkinje cells. Given that the cerebellum is largely fueled by glucose and Purkinje neurons are estimated to spend more energy than Bergmann glial cells, these results suggest substantial shuttling of an energy-rich metabolite like

  9. A note on the definition and the development of cerebellar purkinje cell zones

    NARCIS (Netherlands)

    J. Voogd (Jan)

    2012-01-01

    textabstractThe definition of Purkinje cell zones by their white matter comprtments, their physiological properties, and their molecular identity and the birthdate of their Purkinje cells will be reviewed.

  10. High dosage of monosodium glutamate causes deficits of the motor coordination and the number of cerebellar Purkinje cells of rats.

    Science.gov (United States)

    Prastiwi, D; Djunaidi, A; Partadiredja, G

    2015-11-01

    Monosodium glutamate (MSG) has been widely used throughout the world as a flavoring agent of food. However, MSG at certain dosages is also thought to cause damage to many organs, including cerebellum. This study aimed at investigating the effects of different doses of MSG on the motor coordination and the number of Purkinje cells of the cerebellum of Wistar rats. A total of 24 male rats aged 4 to 5 weeks were divided into four groups, namely, control (C), T2.5, T3, and T3.5 groups, which received intraperitoneal injection of 0.9% sodium chloride solution, 2.5 mg/g body weight (bw) of MSG, 3.0 mg/g bw of MSG, and 3.5 mg/g bw of MSG, respectively, for 10 consecutive days. The motor coordination of the rats was examined prior and subsequent to the treatment. The number of cerebellar Purkinje cells was estimated using physical fractionator method. It has been found that the administration of MSG at a dosage of 3.5 mg/g bw, but not at lower dosages, caused a significant decrease of motor coordination and the estimated total number of Purkinje cells of rats. There was also a significant correlation between motor coordination and the total number of Purkinje cells.

  11. Natural apoptosis in developing mice dopamine midbrain neurons and vermal Purkinje cells.

    Science.gov (United States)

    Martí-Clúa, J

    2016-01-01

    Natural cell death by apoptosis was studied in two neuronal populations of BALB/c, C57BL/6 and B6CBA-Aw-j/A hybrid stock mice: (I) dopaminergic (DA) neurons in choosing coronal levels throughout the anteroposterior extent of the substantia nigra pars compacta (SNc), and (II) Purkinje cells (PCs) in each vermal lobe of the cerebellar cortex. Mice were collected at postnatal day (P) 2 and P14 for the midbrain study, and at P4 and P7 for the analysis of the cerebellum. No DA cells with morphologic criteria for apoptosis were found. Moreover, when the combination of tyrosine hydroxylase and TUNEL or tyrosine hydroxylase and active caspase-3 immunohistochemistry were performed in the same tissue section, no DA cells TUNEL positives or active caspase-3-stained DA neurons were seen. On the other hand, when PCs were considered, data analysis revealed that more dying PCs were observed at P4 than at P7. Values of neuron death were highest in the central lobe; this was followed by the posterior and anterior lobes and then by the inferior lobe. To determine if apoptotic death of PCs is linked to their time-of-origin profiles, pregnant dams were administered with [3H]TdR on embryonic days 11-12, 12-13, 13-14 and 14-15. When TUNEL and [3H]TdR autoradiography or active caspase-3 immunohistochemistry and [3H]TdR autoradiography were combined in the same tissue section, results reveal that the naturally occurring PC death is not related to its time of origin but, rather, is random across age. PMID:27543775

  12. [EXPRESSION OF DOUBLECORTIN AND NeuN IN THE DEVELOPING CEREBELLAR NEURONS IN RAT].

    Science.gov (United States)

    Zimatkin, S M; Karniushko, O A

    2016-01-01

    This work was performed on the offspring of 5 outbred female albino rats to give a comparative immunohistochemical evaluation of doublecortin (DCX) and NeuN expression in the neurons of the cerebellar cortex and nucleus interpositus in the early postnatal ontogenesis (postnatal days 2-15). DCX expression was detected in postmitotic neurons of the external granular layer and migrating neurons of the cerebellar cortex. At postnatal days 2 and 7 DCX expression in neocerebellum was higher than in paleocerebellum. NeuN expression was found to appear in migrating granule neurons, and reach the maximum in mature neurons of internal granular layer. DCX expression was not detected in Purkinje cells and in the nucleus interpositus of the cerebellum. In neurons of the nucleus interpositus the expression of NeuN progressively increased from postnatal days 2 to 15. Thus, a comparative immunohistochemical study of the dynamics of the expression of the pair of molecular markers studied proved to be an effective way of the assessment of the development of granular neurons of the cerebellum in early postnatal ontogenesis. PMID:27487661

  13. Physiology, morphology and detailed passive models of guinea-pig cerebellar Purkinje cells.

    Science.gov (United States)

    Rapp, M; Segev, I; Yarom, Y

    1994-01-01

    1. Purkinje cells (PCs) from guinea-pig cerebellar slices were physiologically characterized using intracellular techniques. Extracellular caesium ions were used to linearize the membrane properties of PCs near the resting potential. Under these conditions the average input resistance, RN, was 29 M omega, the average system time constant, tau 0, was 82 ms and the average cable length, LN, was 0.59. 2. Three PCs were fully reconstructed following physiological measurements and staining with horseradish peroxidase. Assuming that each spine has an area of 1 micron 2 and that the spine density over the spiny dendrites is ten spines per micrometre length, the total membrane area of each PC is approximately 150,000 microns 2, of which approximately 100,000 microns 2 is in the spines. 3. Detailed passive cable and compartmental models were built for each of the three reconstructed PCs. Computational methods were devised to incorporate globally the huge number of spines into these models. In all three cells the models predict that the specific membrane resistivity, Rm, of the soma is much lower than the dendritic Rm (approximately 500 and approximately 100,000 omega cm2 respectively). The specific membrane capacitance, Cm, is estimated to be 1.5-2 muF cm-2 and the specific cytoplasm resistivity, Ri, is 250 omega cm. 4. The average cable length of the dendrites according to the model is 0.13 lambda, suggesting that under caesium conditions PCs are electrically very compact. Brief somatic spikes, however, are expected to attenuate 30-fold when spreading passively into the dendritic terminals. A simulated 200 Hz train of fast, 90 mV somatic spikes produced a smooth 12 mV steady depolarization at the dendritic terminals. 5. A transient synaptic conductance increase, with a 1 nS peak at 0.5 ms and a driving force of 60 mV, is expected to produce approximately 20 mV peak depolarization at the spine head membrane. This EPSP then attenuates between 200- and 900-fold into the soma

  14. The 40-year history of modeling active dendrites in cerebellar Purkinje cells: Emergence of the first single cell 'Community Model'

    Directory of Open Access Journals (Sweden)

    James M Bower

    2015-10-01

    Full Text Available The subject of the effects of the active properties of the Purkinje cell dendrite on neuronal function has been an active subject of study for more than 40 years. Somewhat unusually, some of these investigations, from the outset have involved an interacting combination of experimental and model-based techniques. This paper recounts that 40-year history, and the view of the functional significance of the active properties of the Purkinje cell dendrite that has emerged. It specifically considers the emergence from these efforts of what is arguably the first single cell ‘community’ model in neuroscience. The paper also considers the implications of the development of this model for future studies of the complex properties of neuronal dendrites.

  15. Talpid3-binding centrosomal protein Cep120 is required for centriole duplication and proliferation of cerebellar granule neuron progenitors.

    Directory of Open Access Journals (Sweden)

    Chuanqing Wu

    Full Text Available Granule neuron progenitors (GNPs are the most abundant neuronal type in the cerebellum. GNP proliferation and thus cerebellar development require Sonic hedgehog (Shh secreted from Purkinje cells. Shh signaling occurs in primary cilia originating from the mother centriole. Centrioles replicate only once during a typical cell cycle and are responsible for mitotic spindle assembly and organization. Recent studies have linked cilia function to cerebellar morphogenesis, but the role of centriole duplication in cerebellar development is not known. Here we show that centrosomal protein Cep120 is asymmetrically localized to the daughter centriole through its interaction with Talpid3 (Ta3, another centrosomal protein. Cep120 null mutant mice die in early gestation with abnormal heart looping. Inactivation of Cep120 in the central nervous system leads to both hydrocephalus, due to the loss of cilia on ependymal cells, and severe cerebellar hypoplasia, due to the failed proliferation of GNPs. The mutant GNPs lack Hedgehog pathway activity. Cell biological studies show that the loss of Cep120 results in failed centriole duplication and consequently ciliogenesis, which together underlie Cep120 mutant cerebellar hypoplasia. Thus, our study for the first time links a centrosomal protein necessary for centriole duplication to cerebellar morphogenesis.

  16. The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells

    Directory of Open Access Journals (Sweden)

    Séverine M. Sigoillot

    2015-02-01

    Full Text Available Precise patterns of connectivity are established by different types of afferents on a given target neuron, leading to well-defined and non-overlapping synaptic territories. What regulates the specific characteristics of each type of synapse, in terms of number, morphology, and subcellular localization, remains to be understood. Here, we show that the signaling pathway formed by the secreted complement C1Q-related protein C1QL1 and its receptor, the adhesion-GPCR brain angiogenesis inhibitor 3 (BAI3, controls the stereotyped pattern of connectivity established by excitatory afferents on cerebellar Purkinje cells. The BAI3 receptor modulates synaptogenesis of both parallel fiber and climbing fiber afferents. The restricted and timely expression of its ligand C1QL1 in inferior olivary neurons ensures the establishment of the proper synaptic territory for climbing fibers. Given the broad expression of C1QL and BAI proteins in the developing mouse brain, our study reveals a general mechanism contributing to the formation of a functional brain.

  17. Intracellular correlates of acquisition and long-term memory of classical conditioning in Purkinje cell dendrites in slices of rabbit cerebellar lobule HVI.

    Science.gov (United States)

    Schreurs, B G; Gusev, P A; Tomsic, D; Alkon, D L; Shi, T

    1998-07-15

    Intradendritic recordings in Purkinje cells from a defined area in parasaggital slices of cerebellar lobule HVI, obtained after rabbits were given either paired (classical conditioning) or explicitly unpaired (control) presentations of tone and periorbital electrical stimulation, were used to assess the nature and duration of conditioning-specific changes in Purkinje cell dendritic membrane excitability. We found a strong relationship between the level of conditioning and Purkinje cell dendritic membrane excitability after initial acquisition of the conditioned response. Moreover, conditioning-specific increases in Purkinje cell excitability were still present 1 month after classical conditioning. Although dendritically recorded membrane potential, input resistance, and amplitude of somatic and dendritic spikes were not different in cells from paired or control animals, the size of a potassium channel-mediated transient hyperpolarization was significantly smaller in cells from animals that received classical conditioning. In slices of lobule HVI obtained from naive rabbits, the conditioning-related increases in membrane excitability could be mimicked by application of potassium channel antagonist tetraethylammonium chloride, iberiotoxin, or 4-aminopyridine. However, only 4-aminopyridine was able to reduce the transient hyperpolarization. The pharmacological data suggest a role for potassium channels and, possibly, channels mediating an IA-like current, in learning-specific changes in membrane excitability. The conditioning-specific increase in Purkinje cell dendritic excitability produces an afterhyperpolarization, which is hypothesized to release the cerebellar deep nuclei from inhibition, allowing conditioned responses to be elicited via the red nucleus and accessory abducens motorneurons.

  18. Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Hasegawa Akira

    2011-02-01

    Full Text Available Abstract The patient was an 84-year-old woman who had the onset of truncal ataxia at age 77 and a history of Basedow's disease. Her ataxic gait gradually deteriorated. She could not walk without support at age 81 and she was admitted to our hospital at age 83. Gaze-evoked nystagmus and dysarthria were observed. Mild ataxia was observed in all limbs. Her deep tendon reflex and sense of position were normal. IgA anti-gliadin antibody, IgG anti-gliadin antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody and anti-TPO antibody were positive. A conventional brain MRI did not show obvious cerebellar atrophy. However, MRI voxel based morphometry (VBM and SPECT-eZIS revealed cortical cerebellar atrophy and reduced cerebellar blood flow. IVIg treatment was performed and was moderately effective. After her death at age 85, the patient was autopsied. Neuropathological findings were as follows: selective loss of Purkinje cells; no apparent degenerative change in the efferent pathways, such as the dentate nuclei or vestibular nuclei; no prominent inflammatory reaction. From these findings, we diagnosed this case as autoimmune cerebellar atrophy associated with gluten ataxia. All 3 autopsies previously reported on gluten ataxia have noted infiltration of inflammatory cells in the cerebellum. In this case, we postulated that the infiltration of inflammatory cells was not found because the patient's condition was based on humoral immunity. The clinical conditions of gluten ataxia have not yet been properly elucidated, but are expected to be revealed as the number of autopsied cases increases.

  19. Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes.

    Science.gov (United States)

    Zagha, Edward; Manita, Satoshi; Ross, William N; Rudy, Bernardo

    2010-06-01

    Purkinje cell dendrites are excitable structures with intrinsic and synaptic conductances contributing to the generation and propagation of electrical activity. Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. Moreover, mutations in Kv3.3 cause movement disorders in mice and cerebellar atrophy and ataxia in humans, emphasizing the importance of understanding the role of these channels. In this study, we explore functional implications of this dendritic channel expression and compare Purkinje cell dendritic excitability in wild-type and Kv3.3 knockout mice. We demonstrate enhanced excitability of Purkinje cell dendrites in Kv3.3 knockout mice, despite normal resting membrane properties. Combined data from local application pharmacology, voltage clamp analysis of ionic currents, and assessment of dendritic Ca(2+) spike threshold in Purkinje cells suggest a role for Kv3.3 channels in opposing Ca(2+) spike initiation. To study the physiological relevance of altered dendritic excitability, we measured [Ca(2+)](i) changes throughout the dendritic tree in response to climbing fiber activation. Ca(2+) signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca(2+) influx in distal dendrites. These findings characterize unique roles of Kv3.3 channels in dendrites, with implications for synaptic integration, plasticity, and human disease. PMID:20357073

  20. Synchrony and neural coding in cerebellar circuits

    Directory of Open Access Journals (Sweden)

    Abigail L Person

    2012-12-01

    Full Text Available The cerebellum regulates complex movements and is also implicated in cognitive tasks, and cerebellar dysfunction is consequently associated not only with movement disorders, but also with conditions like autism and dyslexia. How information is encoded by specific cerebellar firing patterns remains debated, however. A central question is how the cerebellar cortex transmits its integrated output to the cerebellar nuclei via GABAergic synapses from Purkinje neurons. Possible answers come from accumulating evidence that subsets of Purkinje cells synchronize their firing during behaviors that require the cerebellum. Consistent with models predicting that coherent activity of inhibitory networks has the capacity to dictate firing patterns of target neurons, recent experimental work supports the idea that inhibitory synchrony may regulate the response of cerebellar nuclear cells to Purkinje inputs, owing to the interplay between unusually fast inhibitory synaptic responses and high rates of intrinsic activity. Data from multiple laboratories lead to a working hypothesis that synchronous inhibitory input from Purkinje cells can set the timing and rate of action potentials produced by cerebellar nuclear cells, thereby relaying information out of the cerebellum. If so, then changing spatiotemporal patterns of Purkinje activity would allow different subsets of inhibitory neurons to control cerebellar output at different times. Here we explore the evidence for and against the idea that a synchrony code defines, at least in part, the input-output function between the cerebellar cortex and nuclei. We consider the literature on the existence of simple spike synchrony, convergence of Purkinje neurons onto nuclear neurons, and intrinsic properties of nuclear neurons that contribute to responses to inhibition. Finally, we discuss factors that may disrupt or modulate a synchrony code and describe the potential contributions of inhibitory synchrony to other motor

  1. Does cerebellar neuronal integrity relate to cognitive ability?

    International Nuclear Information System (INIS)

    Full text: Magnetic resonance spectroscopy (MRS) allows the non-invasive measurement of metabolite levels in the brain. One of these is N-acetylaspartate (NA), a molecule found solely in neurones, synthesised there by mitochondria. This compound can be considered as a marker of 1) neuronal density and 2) neuronal mitochondria function. We recently completed a joint MRS and neuropsychological investigation of Williams-Beuren syndrome (WBS), a rare (1/20,000) autosomal dominant disorder caused by a deletion which includes the elastin locus and LIM-kinase. The syndrome has an associated behavioural and cognitive profile which includes hyperactivity, hyperacusis and excessive sociability. Spatial skills are severely affected, while verbal skills are left relatively intact Our investigation showed loss of NA from the cerebellum in WBS compared with normal controls, with the subject population as a whole displaying a continuum of cerebellar NA concentration. Ability at cognitive tests, including the Weschler IQ scale and various verbal and spatial tests, was shown to correlate significantly and positively with the concentration of NA in the cerebellum. This finding can be interpreted in one of two ways: 1. Our sampling of cerebellar metabolite levels represents a 'global' sampling of total brain neuronal density and, as such, is independent of cerebellar integrity. 2. Cerebellar neuronal integrity is associated with performance at cognitive tests. If the latter interpretation is shown to be the case, it will have important implications for our current understanding of cerebellar function. Copyright (1998) Australian Neuroscience Society

  2. Facial stimulation induces long-term depression at cerebellar molecular layer interneuron–Purkinje cell synapses in vivo in mice

    Directory of Open Access Journals (Sweden)

    De-Lai eQiu

    2015-06-01

    Full Text Available Cerebellar long-term synaptic plasticity has been proposed to provide a cellular mechanism for motor learning. Numerous studies have demonstrated the induction and mechanisms of synaptic plasticity at parallel fiber–Purkinje cell (PF–PC, parallel fiber–molecular layer interneurons (PF–MLI and mossy fiber–granule cell (MF–GC synapses, but no study has investigated sensory stimulation-evoked synaptic plasticity at MLI–PC synapses in the cerebellar cortex of living animals. We studied the expression and mechanism of MLI–PC GABAergic synaptic plasticity induced by a train of facial stimulation in urethane-anesthetized mice by cell-attached recordings and pharmacological methods. We found that 1 Hz, but not a 2 Hz or 4 Hz, facial stimulation induced a long-term depression (LTD of GABAergic transmission at MLI–PC synapses, which was accompanied with a decrease in the stimulation-evoked pause of spike firing in PCs, but did not induce a significant change in the properties of the sensory-evoked spike events of MLIs. The MLI–PC GABAergic LTD could be prevented by blocking cannabinoid type 1 (CB1 receptors, and could be pharmacologically induced by a CB1 receptor agonist. Additionally, 1 Hz facial stimulation delivered in the presence of a metabotropic glutamate receptor 1 (mGluR1 antagonist, JNJ16259685, still induced the MLI–PC GABAergic LTD, whereas blocking N-methyl-D-aspartate (NMDA receptors during 1 Hz facial stimulation abolished the expression of MLI–PC GABAergic LTD. These results indicate that sensory stimulation can induce an endocannabinoid (eCB-dependent LTD of GABAergic transmission at MLI–PC synapses via activation of NMDA receptors in cerebellar cortical Crus II in vivo in mice. Our results suggest that the sensory stimulation-evoked MLI–PC GABAergic synaptic plasticity may play a critical role in motor learning in animals.

  3. Synaptic responses evoked by tactile stimuli in Purkinje cells in mouse cerebellar cortex Crus II in vivo.

    Directory of Open Access Journals (Sweden)

    Chun-Ping Chu

    Full Text Available BACKGROUND: Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air-puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice. METHODS AND MAIN RESULTS: Thirty-three PCs were recorded from 48 urethane-anesthetized adult (6-8-week-old HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0, the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs in the somata of PCs. Application of SR95531, a specific GABA(A receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation. CONCLUSIONS: These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA(A receptor-mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice.

  4. Interaction between Purkinje cells and inhibitory interneurons may create adjustable output waveforms to generate timed cerebellar output.

    Directory of Open Access Journals (Sweden)

    Simon Hong

    Full Text Available We develop a new model that explains how the cerebellum may generate the timing in classical delay eyeblink conditioning. Recent studies show that both Purkinje cells (PCs and inhibitory interneurons (INs have parallel signal processing streams with two time scales: an AMPA receptor-mediated fast process and a metabotropic glutamate receptor (mGluR-mediated slow process. Moreover, one consistent finding is an increased excitability of PC dendrites (in Larsell's lobule HVI in animals when they acquire the classical delay eyeblink conditioning naturally, in contrast to in vitro studies, where learning involves long-term depression (LTD. Our model proposes that the delayed response comes from the slow dynamics of mGluR-mediated IP3 activation, and the ensuing calcium concentration change, and not from LTP/LTD. The conditioned stimulus (tone, arriving on the parallel fibers, triggers this slow activation in INs and PC spines. These excitatory (from PC spines and inhibitory (from INs signals then interact at the PC dendrites to generate variable waveforms of PC activation. When the unconditioned stimulus (puff, arriving on the climbing fibers, is coupled frequently with this slow activation the waveform is amplified (due to an increased excitability and leads to a timed pause in the PC population. The disinhibition of deep cerebellar nuclei by this timed pause causes the delayed conditioned response. This suggested PC-IN interaction emphasizes a richer role of the INs in learning and also conforms to the recent evidence that mGluR in the cerebellar cortex may participate in slow motor execution. We show that the suggested mechanism can endow the cerebellar cortex with the versatility to learn almost any temporal pattern, in addition to those that arise in classical conditioning.

  5. Vitamin E is essential for Purkinje neuron integrity

    OpenAIRE

    Ulatowski, L.; Parker, R.; Warrier, G.; Sultana, R.; Butterfield, D.A.; Manor, D.

    2013-01-01

    Alpha-tocopherol (vitamin E) is an essential dietary antioxidant with important neuroprotective functions. Alpha-tocopherol deficiency manifests primarily in neurological pathologies, notably cerebellar dysfunctions such as spinocerebellar ataxia. To study the roles of α-tocopherol in the cerebellum, we used the Ttpa-/- mice which lack the tocopherol transfer protein (TTP) and are a faithful model of vitamin E deficiency and oxidative stress. When fed vitamin E deficient diet, Ttpa-/- mice ha...

  6. Cytosolic PLA2(alpha) activation in Purkinje neurons and its role in AMPA-receptor trafficking.

    Science.gov (United States)

    Mashimo, Masato; Hirabayashi, Tetsuya; Murayama, Toshihiko; Shimizu, Takao

    2008-09-15

    Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) selectively releases arachidonic acid from membrane phospholipids and has been proposed to be involved in the induction of long-term depression (LTD), a form of synaptic plasticity in the cerebellum. This enzyme requires two events for its full activation: Ca(2+)-dependent translocation from the cytosol to organelle membranes in order to access phospholipids as substrates, and phosphorylation by several kinases. However, the subcellular distribution and activation of cPLA(2)alpha in Purkinje cells and the role of arachidonic acid in cerebellar LTD have not been fully elucidated. In cultured Purkinje cells, stimulation of AMPA receptors, but not metabotropic glutamate receptors, triggered translocation of cPLA(2)alpha to the somatic and dendritic Golgi compartments. This translocation required Ca(2+) influx through P-type Ca(2+) channels. AMPA plus PMA, a chemical method for inducing LTD, released arachidonic acid via phosphorylation of cPLA(2)alpha. AMPA plus PMA induced a decrease in surface GluR2 for more than 2 hours. Interestingly, this reduction was occluded by a cPLA(2)alpha-specific inhibitor. Furthermore, PMA plus arachidonic acid caused the prolonged internalization of GluR2 without activating AMPA receptors. These results suggest that cPLA(2)alpha regulates the persistent decrease in the expression of AMPA receptors, underscoring the role of cPLA(2)alpha in cerebellar LTD. PMID:18713832

  7. Alcohol impairs long-term depression at the cerebellar parallel fiber-Purkinje cell synapse

    NARCIS (Netherlands)

    A. Belmeguenai; P. Botta (Paolo); J.T. Weber (John); M. Carta (Mario); M.M. de Ruiter (Martijn); C.I. de Zeeuw (Chris); C.F. Valenzuela (Fernando); C.R.W. Hansel (Christian)

    2008-01-01

    textabstractAcute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cere

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  1. File list: Unc.Neu.20.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  10. File list: His.Neu.20.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. Short-term modulation of cerebellar Purkinje cell activity after spontaneous climbing fiber input.

    Science.gov (United States)

    Sato, Y; Miura, A; Fushiki, H; Kawasaki, T

    1992-12-01

    1. There are two opposite points of view concerning the way climbing fiber input in a Purkinje cell modifies simple spike (SS) activity transiently: depression versus enhancement of SS activity. The different groups of investigators favored one effect predominating over the other. In the decerebrate unanesthetized cat, we recorded spontaneous activity of single Purkinje cells and investigated time course of SS activity after the complex spike (CS). 2. In the peri-CS time histogram, there was a SS pause lasting, on average, 10.8 ms after onset of the CS in all of the 316 cells recorded. The pause was followed by a rapid increase in SS activity to a maximum, which was on average 175.6% of a pre-CS control level, and a gradual return to around the control level in the majority of the cells recorded (pause-facilitation type, 71.2%). The increase in SS activity was significant (P SS activity during the 20-100 ms was, on average, 163.7% of the control level. In some cells (pure-pause type, 25.3%), no significant changes were found (P > 0.01) in the post-pause SS firing. In contrast, only 3.5% of the cells (pause-reduction type) showed a significant (P 0.01) in the SS activity between pre-CS periods in all of the cells recorded, suggesting that the SS activity enhancement is not due to a coactivated mossy fiber input just preceding the activation of the climbing fiber input. 4. Analysis of the raster diagram revealed variability of individual SS responses after the CS. The probability of occurrence of the increase in SS number during a post-CS period of 0-100 ms with respect to that during a pre-CS period of -100-0 ms in individual raster traces was high (on average 78.2%), medium (57.3%), and low (36.3%) in the pause-facilitation, pure-pause, and pause-reduction types of the cell, respectively. 5. Nonsequential time histograms showing frequency distribution of the pause duration after the CS in individual raster traces and that showing interspike intervals of the SS were

  12. Cerebellar nuclei neurons show only small excitatory responses to optogenetic olivary stimulation in transgenic mice: in vivo and in vitro studies

    Directory of Open Access Journals (Sweden)

    Huo eLu

    2016-03-01

    Full Text Available To study the olivary input to the cerebellar nuclei (CN we used optogenetic stimulation in transgenic mice expressing channelrhodopsin-2 (ChR2 in olivary neurons. We obtained in vivo extracellular Purkinje cell (PC and CN recordings in anesthetized mice while stimulating the contralateral inferior olive (IO with a blue laser (single pulse, 10 - 50 ms duration. Peri-stimulus histograms were constructed to show the spike rate changes after optical stimulation. Among 29 CN neurons recorded, 15 showed a decrease in spike rate of variable strength and duration, and only 1 showed a transient spiking response. These results suggest that direct olivary input to CN neurons is usually overridden by stronger Purkinje cell inhibition triggered by climbing fiber responses. To further investigate the direct input from the climbing fiber collaterals we also conducted whole cell recordings in brain slices, where we used local stimulation with blue light. Due to the expression of ChR2 in Purkinje cell axons as well as the IO in our transgenic line, strong inhibitory responses could be readily triggered with optical stimulation (13 of 15 neurons. After blocking this inhibition with GABAzine, only in 5 of 13 CN neurons weak excitatory responses were revealed. Therefore our in vitro results support the in vivo findings that the excitatory input to CN neurons from climbing fiber collaterals in adult mice is masked by the inhibition under normal conditions.

  13. Lack of Kinase Regulation of Canonical Transient Receptor Potential 3 (TRPC3) Channel-dependent Currents in Cerebellar Purkinje Cells

    OpenAIRE

    Nelson, Charmaine; Glitsch, Maike D.

    2011-01-01

    Background: TRPC3 channels are inhibited by PKC and PKG, which also induce cerebellar LTD. We investigate if PKC- and PKG-mediated modulation of cerebellar TRPC3 channels contributes to cerebellar LTD.

  14. Studying cerebellar circuits by remote control of selected neuronal types with GABA-A receptors

    Directory of Open Access Journals (Sweden)

    William Wisden

    2009-12-01

    Full Text Available Although GABA-A receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs has been studied intensely on the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioral level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABA-A receptors from Purkinje cells (PC-Δγ2 mice. We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR, presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice showed no ataxia or gait abnormalities suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system has found a way to compensate for its loss. To investigate the latter possibility we have developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice. Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapse to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input, and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view.

  15. Coordinated scaling of cortical and cerebellar numbers of neurons

    Directory of Open Access Journals (Sweden)

    Suzana Herculano-Houzel

    2010-03-01

    Full Text Available While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species – an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of 4 different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora, Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble.

  16. Altered dendritic development of cerebellar Purkinje cells in slice cultures from protein kinase C gamma-deficient mice

    NARCIS (Netherlands)

    Schrenk, K; Kapfhammer, JP; Metzger, F

    2002-01-01

    Protein kinase C (PKC) is a key molecule for the expression of long-term depression at the parallel fiber-Purkinje cell synapse in the cerebellum, a well known model for synaptic plasticity, We have recently shown that activity of PKC also profoundly affects the dendritic morphology of Purkinje cell

  17. The output signal of Purkinje cells of the cerebellum and circadian rhythmicity.

    Directory of Open Access Journals (Sweden)

    Jérôme Mordel

    Full Text Available Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons.

  18. Pairing of pre- and postsynaptic activities in cerebellar Purkinje cells induces long-term changes in synaptic efficacy in vitro.

    Science.gov (United States)

    Crepel, F; Jaillard, D

    1991-01-01

    1. An in vitro slice preparation of rat cerebellar cortex was used to analyse long-lasting modifications of synaptic transmission at parallel fibre (PF)-Purkinje cell (PC) synapses. These use-dependent changes were induced by pairing PF-mediated EPSPs evoked at low frequency (1 Hz) with different levels of membrane polarization (or bioelectrical activities) of PCs for 15 min. 2. Experiments were performed on forty-eight PCs recorded intracellularly in a conventional perfused chamber, and in fifty other cells maintained in a static chamber either in the presence (n = 21) or in the absence (n = 29) of 400 nM-phorbol 12,13-dibutyrate (PDBu). 3. In these three experimental conditions, PF-mediated EPSPs were always measured on PCs maintained at a holding potential of -75 mV, and further hyperpolarized by constant hyperpolarizing pulses. This allowed us both to test the input resistance of PCs and to avoid their firing during PF-mediated EPSPs. 4. In all cells retained for the present study, latencies of PF-mediated EPSPs evoked at 0.2 Hz were stable during the pre-pairing period, and the same was true for their amplitude and time course. 5. In the perfused chamber, pairing of PF-mediated EPSPs with the same hyperpolarization of PCs as that used for measurements of synaptic responses had no effect on these EPSPs in 30% of PCs. It induced long-term depression (LTD) and long-term potentiation (LTP) in 23 and 47% of the tested cells respectively (n = 17). 6. In the perfused chamber, pairing of PF-mediated EPSPs with moderate depolarization of PCs (n = 19) giving rise to a sustained firing of sodium spikes significantly favoured the appearance of LTP as compared to the previous pairing protocol. However, there were still 27 and 15% of cells which showed no modification and LTD respectively. 7. In contrast, pairing of PF-mediated EPSPs with calcium (Ca2+) spikes evoked by strong depolarization of PCs (n = 12) led to LTD of synaptic transmission in nearly half of the tested

  19. Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice.

    Science.gov (United States)

    Schreurs, B G; Oh, M M; Alkon, D L

    1996-03-01

    1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of classical conditioning.

  20. Propofol facilitates excitatory inputs of cerebellar Purkinje cells by depressing molecular layer interneuron activity during sensory information processing in vivo in mice.

    Science.gov (United States)

    He, Yuan-Yuan; Jin, Ri; Jin, Wen-Zhe; Liu, Heng; Chu, Chun-Ping; Qiu, De-Lai

    2015-10-21

    Propofol is a rapid-acting sedative-hypnotic medication that has been widely used for the induction and maintenance of anesthesia; it has specific actions on different areas of the brain, such as sensory information transmission in the somatosensory cortex. However, the effects of propofol on the properties of sensory stimulation-evoked responses in cerebellar Purkinje cells (PCs) are currently unclear. In the present study, we studied the effects of propofol on facial stimulation-evoked responses in cerebellar PCs and molecular level interneurons (MLIs) in urethane-anesthetized mice using electrophysiological and pharmacological methods. Our results showed that cerebellar surface perfusion with propofol induced a decrease in the amplitude of the gamma-aminobutyric acid (GABA)-ergic component (P1) in a dose-dependent manner, but induced a significant increase in the amplitude of the excitatory response (N1). The IC50 of propofol-induced inhibition of P1 was 217.3 μM. In contrast, propofol (100 μM) depressed the spontaneous activity and tactile-evoked responses in MLIs. In addition, blocking GABA(A) receptor activity abolished the propofol (300 μM)-induced inhibition of the tactile-evoked inhibitory response and the increase in the sensory stimulation-evoked spike firing rate of PCs. These results indicated that propofol depressed the tactile stimulation-evoked spike firing of MLIs, resulting in a decrease in the amplitude of the tactile-evoked inhibitory response and an increase in the amplitude of the excitatory response in the cerebellar PCs of mice. Our results suggest that propofol modulates sensory information processing in cerebellar cortical PCs and MLIs through the activation of GABA(A) receptors. PMID:26317477

  1. Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons.

    Science.gov (United States)

    Yamada, Mayumi; Seto, Yusuke; Taya, Shinichiro; Owa, Tomoo; Inoue, Yukiko U; Inoue, Takayoshi; Kawaguchi, Yoshiya; Nabeshima, Yo-Ichi; Hoshino, Mikio

    2014-04-01

    In the cerebellum, the bHLH transcription factors Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions, the ventricular zone (VZ) and the rhombic lip (RL), and are required for producing GABAergic and glutamatergic neurons, respectively. However, it is unclear whether Ptf1a or Atoh1 is sufficient for specifying GABAergic or glutamatergic neuronal fates. To test this, we generated two novel knock-in mouse lines, Ptf1a(Atoh1) and Atoh1(Ptf1a), that are designed to express Atoh1 and Ptf1a ectopically in the VZ and RL, respectively. In Ptf1a(Atoh1) embryos, ectopically Atoh1-expressing VZ cells produced glutamatergic neurons, including granule cells and deep cerebellar nuclei neurons. Correspondingly, in Atoh1(Ptf1a) animals, ectopically Ptf1a-expressing RL cells produced GABAergic populations, such as Purkinje cells and GABAergic interneurons. Consistent results were also obtained from in utero electroporation of Ptf1a or Atoh1 into embryonic cerebella, suggesting that Ptf1a and Atoh1 are essential and sufficient for GABAergic versus glutamatergic specification in the neuroepithelium. Furthermore, birthdating analyses with BrdU in the knock-in mice or with electroporation studies showed that ectopically produced fate-changed neuronal types were generated at temporal schedules closely simulating those of the wild-type RL and VZ, suggesting that the VZ and RL share common temporal information. Observations of knock-in brains as well as electroporated brains revealed that Ptf1a and Atoh1 mutually negatively regulate their expression, probably contributing to formation of non-overlapping neuroepithelial domains. These findings suggest that Ptf1a and Atoh1 specify spatial identities of cerebellar neuron progenitors in the neuroepithelium, leading to appropriate production of GABAergic and glutamatergic neurons, respectively.

  2. File list: InP.Neu.50.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Neu.50.AllAg.Cerebellar_granule_neurons mm9 Input control Neural Cerebellar gran...ule neurons http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Neu.50.AllAg.Cerebellar_granule_neurons.bed ...

  3. File list: NoD.Neu.10.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: InP.Neu.05.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  5. File list: NoD.Neu.05.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: InP.Neu.10.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: InP.Neu.20.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Neu.20.AllAg.Cerebellar_granule_neurons mm9 Input control Neural Cerebellar gran...ule neurons http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Neu.20.AllAg.Cerebellar_granule_neurons.bed ...

  8. File list: NoD.Neu.20.AllAg.Cerebellar_granule_neurons [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Neu.20.AllAg.Cerebellar_granule_neurons mm9 No description Neural Cerebellar gran...ule neurons http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/NoD.Neu.20.AllAg.Cerebellar_granule_neurons.bed ...

  9. Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1 in normal and transformed cerebellar cells

    Directory of Open Access Journals (Sweden)

    Baader Stephan L

    2007-10-01

    Full Text Available Abstract Background Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens. Results During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site. Conclusion Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.

  10. Possible role of pineal allopregnanolone in Purkinje cell survival

    OpenAIRE

    Haraguchi, Shogo; Hara, Sakurako; Ubuka, Takayoshi; Mita, Masatoshi; Tsutsui, Kazuyoshi

    2012-01-01

    It is believed that neurosteroids are produced in the brain and other nervous systems. Here, we show that allopregnanolone (ALLO), a neurosteroid, is exceedingly produced in the pineal gland compared with the brain and that pineal ALLO acts on the Purkinje cell, a principal cerebellar neuron, to prevent apoptosis in the juvenile quail. We first demonstrated that the pineal gland is a major organ of neurosteroidogenesis. A series of experiments using molecular and biochemical techniques has fu...

  11. N-methyl-D-Aspartate Receptors Contribute to Complex Spike Signaling in Cerebellar Purkinje Cells: An In vivo Study in Mice.

    Science.gov (United States)

    Liu, Heng; Lan, Yan; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    N-methyl-D-aspartate receptors (NMDARs) are post-synaptically expressed at climbing fiber-Purkinje cell (CF-PC) synapses in cerebellar cortex in adult mice and contributed to CF-PC synaptic transmission under in vitro conditions. In this study, we investigated the role of NMDARs at CF-PC synapses during the spontaneous complex spike (CS) activity in cerebellar cortex in urethane-anesthetized mice, by in vivo whole-cell recording technique and pharmacological methods. Under current-clamp conditions, cerebellar surface application of NMDA (50 μM) induced an increase in the CS-evoked pause of simple spike (SS) firing accompanied with a decrease in the SS firing rate. Under voltage-clamp conditions, application of NMDA enhanced the waveform of CS-evoked inward currents, which expressed increases in the area under curve (AUC) and spikelet number of spontaneous CS. NMDA increased the AUC of spontaneous CS in a concentration-dependent manner. The EC50 of NMDA for increasing AUC of spontaneous CS was 33.4 μM. Moreover, NMDA significantly increased the amplitude, half-width and decay time of CS-evoked after-hyperpolarization (AHP) currents. Blockade of NMDARs with D-(-)-2-amino-5-phosphonopentanoic acid (D-APV, 250 μM) decreased the AUC, spikelet number, and amplitude of AHP currents. In addition, the NMDA-induced enhancement of CS activity could not be observed after α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors were blocked. The results indicated that NMDARs of CF-PC synapses contributed to the spontaneous CS activity by enhancing CS-evoked inward currents and AHP currents. PMID:27445699

  12. Effects of Gadolinium-Based Contrast Agents on Thyroid Hormone Receptor Action and Thyroid Hormone-Induced Cerebellar Purkinje Cell Morphogenesis.

    Science.gov (United States)

    Ariyani, Winda; Iwasaki, Toshiharu; Miyazaki, Wataru; Khongorzul, Erdene; Nakajima, Takahito; Kameo, Satomi; Koyama, Hiroshi; Tsushima, Yoshito; Koibuchi, Noriyuki

    2016-01-01

    Gadolinium (Gd)-based contrast agents (GBCAs) are used in diagnostic imaging to enhance the quality of magnetic resonance imaging or angiography. After intravenous injection, GBCAs can accumulate in the brain. Thyroid hormones (THs) are critical for the development and functional maintenance of the central nervous system. TH actions in brain are mainly exerted through nuclear TH receptors (TRs). We examined the effects of GBCAs on TR-mediated transcription in CV-1 cells using transient transfection-based reporter assay and TH-mediated cerebellar Purkinje cell morphogenesis in primary culture. We also measured the cellular accumulation and viability of Gd after representative GBCA treatments in cultured CV-1 cells. Both linear (Gd-diethylene triamine pentaacetic acid-bis methyl acid, Gd-DTPA-BMA) and macrocyclic (Gd-tetraazacyclododecane tetraacetic acid, Gd-DOTA) GBCAs were accumulated without inducing cell death in CV-1 cells. By contrast, Gd chloride (GdCl3) treatment induced approximately 100 times higher Gd accumulation and significantly reduced the number of cells. Low doses of Gd-DTPA-BMA (10(-8) to 10(-6)M) augmented TR-mediated transcription, but the transcription was suppressed at higher dose (10(-5) to 10(-4)M), with decreased β-galactosidase activity indicating cellular toxicity. TR-mediated transcription was not altered by Gd-DOTA or GdCl3, but the latter induced a significant reduction in β-galactosidase activity at high doses, indicating cellular toxicity. In cerebellar cultures, the dendrite arborization of Purkinje cells induced by 10(-9)M T4 was augmented by low-dose Gd-DTPA-BMA (10(-7)M) but was suppressed by higher dose (10(-5)M). Such augmentation by low-dose Gd-DTPA-BMA was not observed with 10(-9)M T3, probably because of the greater dendrite arborization by T3; however, the arborization by T3 was suppressed by a higher dose of Gd-DTPA-BMA (10(-5)M) as seen in T4 treatment. The effect of Gd-DOTA on dendrite arborization was much weaker

  13. Effects of gadolinium-based contrast agents on thyroid hormone receptor action and thyroid hormone-induced cerebellar Purkinje cell morphogenesis

    Directory of Open Access Journals (Sweden)

    Noriyuki Koibuchi

    2016-08-01

    Full Text Available Gadolinium (Gd-based contrast agents (GBCAs are used in diagnostic imaging to enhance the quality of magnetic resonance imaging or angiography. After intravenous injection, GBCAs can accumulate in the brain. Thyroid hormones (THs are critical to the development and functional maintenance of the central nervous system. TH actions in brain are mainly exerted through nuclear TH receptors (TRs. We examined the effects of GBCAs on TR-mediated transcription in CV-1 cells using transient transfection-based reporter assay and thyroid hormone-mediated cerebellar Purkinje cell morphogenesis in primary culture. We also measured the cellular accumulation and viability of Gd after representative GBCA treatments in cultured CV-1 cells. Both linear (Gd-diethylene triamine pentaacetic acid-bis methyl acid, Gd-DTPA-BMA and macrocyclic (Gd-tetraazacyclododecane tetraacetic acid, Gd-DOTA GBCAs were accumulated without inducing cell death in CV-1 cells. In contrast, Gd chloride (GdCl3 treatment induced approximately 100 times higher Gd accumulation and significantly reduced the number of cells. Low doses of Gd-DTPA-BMA (10−8–10−6 M augmented TR-mediated transcription, but the transcription was suppressed at higher dose (10−5 – 10−4 M, with decreased β-galactosidase activity indicating cellular toxicity. TR-mediated transcription was not altered by Gd-DOTA or GdCl3, but the latter induced a significant reduction in β-galactosidase activity at high doses, indicating cellular toxicity. In cerebellar cultures, the dendrite arborization of Purkinje cells induced by 10-9 M T4 was augmented by low-dose Gd-DTPA-BMA (10−7 M but was suppressed by higher dose (10−5 M. Such augmentation by low-dose Gd-DTPA-BMA was not observed with 10-9 M T3, probably because of the greater dendrite arborization by T3; however, the arborization by T3 was suppressed by a higher dose of Gd-DTPA-BMA (10-5 M as seen in T4 treatment. The effect of Gd-DOTA on dendrite arborization

  14. Effects of Gadolinium-Based Contrast Agents on Thyroid Hormone Receptor Action and Thyroid Hormone-Induced Cerebellar Purkinje Cell Morphogenesis

    Science.gov (United States)

    Ariyani, Winda; Iwasaki, Toshiharu; Miyazaki, Wataru; Khongorzul, Erdene; Nakajima, Takahito; Kameo, Satomi; Koyama, Hiroshi; Tsushima, Yoshito; Koibuchi, Noriyuki

    2016-01-01

    Gadolinium (Gd)-based contrast agents (GBCAs) are used in diagnostic imaging to enhance the quality of magnetic resonance imaging or angiography. After intravenous injection, GBCAs can accumulate in the brain. Thyroid hormones (THs) are critical for the development and functional maintenance of the central nervous system. TH actions in brain are mainly exerted through nuclear TH receptors (TRs). We examined the effects of GBCAs on TR-mediated transcription in CV-1 cells using transient transfection-based reporter assay and TH-mediated cerebellar Purkinje cell morphogenesis in primary culture. We also measured the cellular accumulation and viability of Gd after representative GBCA treatments in cultured CV-1 cells. Both linear (Gd-diethylene triamine pentaacetic acid-bis methyl acid, Gd-DTPA-BMA) and macrocyclic (Gd-tetraazacyclododecane tetraacetic acid, Gd-DOTA) GBCAs were accumulated without inducing cell death in CV-1 cells. By contrast, Gd chloride (GdCl3) treatment induced approximately 100 times higher Gd accumulation and significantly reduced the number of cells. Low doses of Gd-DTPA-BMA (10−8 to 10−6M) augmented TR-mediated transcription, but the transcription was suppressed at higher dose (10−5 to 10−4M), with decreased β-galactosidase activity indicating cellular toxicity. TR-mediated transcription was not altered by Gd-DOTA or GdCl3, but the latter induced a significant reduction in β-galactosidase activity at high doses, indicating cellular toxicity. In cerebellar cultures, the dendrite arborization of Purkinje cells induced by 10−9M T4 was augmented by low-dose Gd-DTPA-BMA (10−7M) but was suppressed by higher dose (10−5M). Such augmentation by low-dose Gd-DTPA-BMA was not observed with 10−9M T3, probably because of the greater dendrite arborization by T3; however, the arborization by T3 was suppressed by a higher dose of Gd-DTPA-BMA (10−5M) as seen in T4 treatment. The effect of Gd-DOTA on dendrite arborization was much weaker

  15. Importance of genetics in fetal alcohol effects: null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits.

    Science.gov (United States)

    Bonthius, Daniel J; Winters, Zachary; Karacay, Bahri; Bousquet, Samantha Larimer; Bonthius, Daniel J

    2015-01-01

    The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS-/- mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS-/- mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS-/- mice and their wild type controls received alcohol (0.0, 2.2, or 4.4mg/g) daily over postnatal days 4-9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS-/- and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS-/- mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS-/- mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS-/- mice, but not in wild type. Thus, homozygous

  16. Nuclear Factor I and Cerebellar Granule Neuron Development: An Intrinsic–Extrinsic Interplay

    OpenAIRE

    Kilpatrick, Daniel L.; Wang, Wei; Gronostajski, Richard; Litwack, E. David

    2012-01-01

    Granule neurons have a central role in cerebellar function via their synaptic interactions with other neuronal cell types both within and outside this structure. Establishment of these synaptic connections and its control is therefore essential to their function. Both intrinsic as well as environmental mechanisms are required for neuronal development and formation of neuronal circuits, and a key but poorly understood question is how these various events are coordinated and integrated in matur...

  17. Comparative neuronal morphology of the cerebellar cortex in afrotherians, carnivores, cetartiodactyls, and primates

    Directory of Open Access Journals (Sweden)

    Bob eJacobs

    2014-04-01

    Full Text Available Although the basic morphological characteristics of neurons in the cerebellar cortex have been documented in several species, virtually nothing is known about the quantitative morphological characteristics of these neurons across different taxa. To that end, the present study investigated cerebellar neuronal morphology among eight different, large-brained mammalian species comprising a broad phylogenetic range: afrotherians (African elephant, Florida manatee, carnivores (Siberian tiger, clouded leopard, cetartiodactyls (humpback whale, giraffe and primates (human, common chimpanzee. Specifically, several neuron types (e.g., stellate, basket, Lugaro, Golgi, and granule neurons; N = 317 of the cerebellar cortex were stained with a modified rapid Golgi technique and quantified on a computer-assisted microscopy system. There was a 64-fold variation in brain mass across species in our sample (from clouded leopard to the elephant and a 103-fold variation in cerebellar volume. Most dendritic measures tended to increase with cerebellar volume. The cerebellar cortex in these species exhibited the trilaminate pattern common to all mammals. Morphologically, neuron types in the cerebellar cortex were generally consistent with those described in primates (Fox et al., 1967 and rodents (Palay and Chan-Palay, 1974, although there was substantial quantitative variation across species. In particular, Lugaro neurons in the elephant appeared to be disproportionately larger than those in other species. To explore potential quantitative differences in dendritic measures across species, MARSplines analyses were used to evaluate whether species could be differentiated from each other based on dendritic characteristics alone. Results of these analyses indicated that there were significant differences among all species in dendritic measures.

  18. Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus.

    Science.gov (United States)

    Yamaguchi, Kazuhiko; Itohara, Shigeyoshi; Ito, Masao

    2016-09-01

    Long-term depression (LTD) of synaptic transmission from parallel fibers (PFs) to a Purkinje cell (PC) in the cerebellum has been considered to be a core mechanism of motor learning. Recently, however, discrepancies between LTD and motor learning have been reported in mice with a mutation that targeted the expression of PF-PC LTD by blocking AMPA-subtype glutamate receptor internalization regulated via the phosphorylation of AMPA receptors. In these mice, motor learning behavior was normal, but no PF-PC LTD was observed. We reexamined slices obtained from these GluA2 K882A and GluA2 Δ7 knockin mutants at 3-6 mo of age. The conventional protocols of stimulation did not induce LTD in these mutant mice, as previously reported, but surprisingly, LTD was induced using certain modified protocols. Such modifications involved increases in the number of PF stimulation (from one to two or five), replacement of climbing fiber stimulation with somatic depolarization (50 ms), filling a patch pipette with a Cs(+)-based solution, or extension of the duration of conjunction. We also found that intracellular infusion of a selective PKCα inhibitor (Gö6976) blocked LTD induction in the mutants, as in WT, suggesting that functional compensation occurred downstream of PKCα. The possibility that LTD in the mutants was caused by changes in membrane resistance, access resistance, or presynaptic property was excluded. The present results demonstrate that LTD is inducible by intensified conjunctive stimulations even in K882A and Δ7 mutants, indicating no contradiction against the LTD hypothesis of motor learning. PMID:27551099

  19. SMAD4 is essential for generating subtypes of neurons during cerebellar development

    OpenAIRE

    Fernandes, Marie; Antoine, Michelle; Hébert, Jean M.

    2012-01-01

    Cerebellum development involves the coordinated production of multiple neuronal cell types. The cerebellar primordium contains two germinative zones, the rhombic lip (RL) and the ventricular zone (VZ), which generate the different types of glutamatergic and GABAergic neurons, respectively. What regulates the specification and production of glutamatergic and GABAergic neurons as well as the subtypes for each of these two broad classes remains largely unknown. Here we demonstrate with condition...

  20. Serotonergic modulation and its influence on signal processing at cellular level in deep cerebellar nuclei neurons

    OpenAIRE

    Lee, Meng-Larn

    2007-01-01

    Deep cerebellar nuclei (DCN) neurons generate the final output of cerebellum and receive abundant modulatory serotonergic inputs from brainstem neurons. The aim of this present study was to elucidate the influence of serotonin on signal processing performed by DCN neurons. Since signal processing is determined by the interplay between intrinsic and synaptic properties, the impact of serotonin on intrinsic as well as synaptic properties was investigated. To this end whole-cell patch clamp reco...

  1. Nitric oxide promotes survival of cerebellar granule neurons cultured in vitro through the Akt pathway

    Institute of Scientific and Technical Information of China (English)

    Lin Wang; Mei Li; Lihua Zhou

    2011-01-01

    In this study, cerebellar granule neurons were used to examine the role of nitric oxide on cell survival. The N-methyl-D-aspartic acid receptor antagonist, MK-801, and the soluble guanylate cyclase antagonist, 1H-[1, 2, 4]oxadiazolo-[4, 3-a] quinoxalin-1-one, decreased cell viability, induced caspase-3, and decreased phosphorylated-Akt levels, suggesting that blockade of nitric oxide production promotes apoptosis of differentiating cerebellar granule neurons. After administration of sodium nitroprusside, an endogenous nitric oxide donor, cell viability recovered,caspase-3 expression was decreased, and phosphorylated-Akt levels increased. This study provides direct evidence that nitric oxide can sustain the survival of developing cerebellar granule neurons in vitro through the nitric oxide-Akt pathway. Moreover, endogenous nitric oxide exerts these effects in a cyclic guanosine monophosphate-dependent manner while exogenous nitric oxide does so in a cyclic guanosine monophosphate-independent manner.

  2. Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.

    Science.gov (United States)

    Chung, Chan; Elrick, Matthew J; Dell'Orco, James M; Qin, Zhaohui S; Kalyana-Sundaram, Shanker; Chinnaiyan, Arul M; Shakkottai, Vikram G; Lieberman, Andrew P

    2016-05-01

    Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC) disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1), promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders. PMID:27152617

  3. Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.

    Directory of Open Access Journals (Sweden)

    Chan Chung

    2016-05-01

    Full Text Available Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1, promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders.

  4. 大鼠小脑颗粒神经元体外原代培养%Primary culture of rat cerebellar granule neurons in vitro

    Institute of Scientific and Technical Information of China (English)

    姚洪菊; 周令望; 裴俊瑞; 刘晓娜; 王静

    2013-01-01

    contrast microscope.Granule cells gradually turned round from oval and outlines became clearer in 2-3 days.In 4-6 days,there were a wide range of synaptic connections among the neurons and a mature nerve cell network formed.A large quantity of cerebellar granule neurons was seen by NSE identification.Few bigger cells such as purkinjes cells and glial cell outlines were also seen in the same visual field.Conclusions This is a successful primary culture method for acquirement of rat cerebellar granule neurons.The method can provide experimental basis for future studies the toxic effects of chronic arsenic exposure on cerebellar cells.

  5. 电鱼小脑浦肯野细胞对急性缺氧的功能反应%Functional responses of mormyrid cerebellar Purkinje cells to acute hypoxia insult

    Institute of Scientific and Technical Information of China (English)

    李晶; 师长宏; 成胜权; 李果; 谭小丽; 杜永平; 张月萍

    2013-01-01

    目的:通过研究急性缺氧对电鱼(mormyrid electric fish)小脑浦肯野细胞(Purkinje cell,PC)的功能影响,阐明缺氧耐受动物神经元在缺氧条件下的电生理特征.方法:采用全细胞膜片钳记录法,观察急性缺氧对电鱼小脑主神经元PC膜电位、兴奋性和平行纤维(parallel fiber,PF)-PC突触传递的影响.结果:(1)短暂缺氧使电鱼小脑PC膜电位发生迅速而持久的超极化,可持续30 min以上,同时伴随自发放电频率的显著下降.谷氨酸AMPA受体阻断剂CNQX不影响PC缺氧性超极化的产生,但可阻断缺氧性超极化的持续存在;而GABAA受体阻断剂Bicuculline则完全阻断缺氧性超极化的产生,并使膜电位在缺氧开始后发生短暂的去极化.(2)缺氧使PC诱发动作电位的阈值增高,频率减低,幅值减小.(3)急性缺氧使刺激PF诱发的PC兴奋性突触后电流(excitatory postsynaptic current,EPSC)呈现长时程增强(long term potentiation,LTP),同时使EPSC双脉冲增强现象(pair-pulse facilitation,PPF)显著衰减.CNQX逆转了PF EPSC的缺氧性LTP,表现为长时程抑制(Long Term Depression,LTD);而Bicuculline则使PF EPSC的缺氧性LTP增强.结论:耐缺氧动物电鱼小脑神经元的缺氧反应特征与哺乳类动物显著不同,AMPA受体和GABAA受体均参与电鱼小脑PC的缺氧性超极化和PF LTP的产生,表明维持GABA能突触和谷氨酸能突触活动的适度平衡,可能是电鱼以及其他耐缺氧动物脑保护机制的关键.%Objective: To evaluate the electrophysiological characteristics of neuron in anorexia tolerant animal under hypoxia condition by discovering the functional responses of Mormyrid cerebellar Purkinje cells (PCs) to acute hypoxia insult. Methods: The whole cell patch clamp was used for the intracellular recording from PCs of the mormyrid cerebellar slices to evaluate the changes of the membrane potential and the excitability of PCs and the PF-PC synaptic transmission induced by acute

  6. A new approach for determining phase response curves reveals that Purkinje cells can act as perfect integrators.

    Directory of Open Access Journals (Sweden)

    Elena Phoka

    2010-04-01

    Full Text Available Cerebellar Purkinje cells display complex intrinsic dynamics. They fire spontaneously, exhibit bistability, and via mutual network interactions are involved in the generation of high frequency oscillations and travelling waves of activity. To probe the dynamical properties of Purkinje cells we measured their phase response curves (PRCs. PRCs quantify the change in spike phase caused by a stimulus as a function of its temporal position within the interspike interval, and are widely used to predict neuronal responses to more complex stimulus patterns. Significant variability in the interspike interval during spontaneous firing can lead to PRCs with a low signal-to-noise ratio, requiring averaging over thousands of trials. We show using electrophysiological experiments and simulations that the PRC calculated in the traditional way by sampling the interspike interval with brief current pulses is biased. We introduce a corrected approach for calculating PRCs which eliminates this bias. Using our new approach, we show that Purkinje cell PRCs change qualitatively depending on the firing frequency of the cell. At high firing rates, Purkinje cells exhibit single-peaked, or monophasic PRCs. Surprisingly, at low firing rates, Purkinje cell PRCs are largely independent of phase, resembling PRCs of ideal non-leaky integrate-and-fire neurons. These results indicate that Purkinje cells can act as perfect integrators at low firing rates, and that the integration mode of Purkinje cells depends on their firing rate.

  7. Two forms of cerebellar glial cells interact differently with neurons in vitro

    OpenAIRE

    1984-01-01

    Specific interactions between neurons and glia dissociated from early postnatal mouse cerebellar tissue were studied in vitro by indirect immunocytochemical staining with antisera raised against purified glial filament protein, galactocerebroside, and the NILE glycoprotein. Two forms of cells were stained with antisera raised against purified glial filament protein. The first, characterized by a cell body 9 microns diam and processes 130-150 microns long, usually had two to three neurons asso...

  8. Projections of individual Purkinje cells of identified zones in the ventral nodulus to the vestibular and cerebellar nuclei in the rabbit.

    Science.gov (United States)

    Wylie, D R; De Zeeuw, C I; DiGiorgi, P L; Simpson, J I

    1994-11-15

    The projections of Purkinje cells from zones in the ventral nodulus of pigmented rabbits were studied with the use of extracellularly injected biocytin as an anterograde tracer. The zones were physiologically identified according to the complex spike modulation of Purkinje cells in response to optokinetic stimulation. Purkinje cells in the most medial zone do not respond to optokinetic stimulation; they project to the fastigial nucleus, the perifastigial white matter, the periinterposed white matter, and the medial vestibular nucleus. In the adjacent zone, Purkinje cells respond best to optokinetic stimulation about the vertical axis; they project to the periinterposed white matter and the medial vestibular nucleus. Purkinje cells in the next zone respond best to optokinetic stimulation about an axis approximately perpendicular to the ipsilateral anterior canal; they project to the periinterposed white matter, dorsal group y, the superior vestibular nucleus, and the medial vestibular nucleus. In the most lateral zone, Purkinje cells respond best to optokinetic stimulation about the vertical axis; they project to the periinterposed white matter, dorsal group y, and the medial vestibular nucleus. The majority of axons gave off collaterals and innervated more than one nucleus. Often, three or four different areas received terminals from a single Purkinje cell axon. The zonal projection pattern of the ventral nodulus is compared to that of the flocculus, which, with respect to the visual climbing fiber afferents, has similar zones.

  9. Cerebellar stem cells do not produce neurons and astrocytes in adult mouse

    Energy Technology Data Exchange (ETDEWEB)

    Su, Xin; Guan, Wuqiang; Yu, Yong-Chun; Fu, Yinghui, E-mail: fuyh@fudan.edu.cn

    2014-07-18

    Highlights: • No new neurons and astrocytes are generated in adult mouse cerebellum. • Very few mash1{sup +} or nestin{sup +} stem cells exist, and most of them are quiescent. • Cell proliferation rate is diversified among cerebellar regions and decreases over time. - Abstract: Although previous studies implied that cerebellar stem cells exist in some adult mammals, little is known about whether these stem cells can produce new neurons and astrocytes. In this study by bromodeoxyuridine (BrdU) intraperitoneal (i.p.) injection, we found that there are abundant BrdU{sup +} cells in adult mouse cerebellum, and their quantity and density decreases significantly over time. We also found cell proliferation rate is diversified in different cerebellar regions. Among these BrdU{sup +} cells, very few are mash1{sup +} or nestin{sup +} stem cells, and the vast majority of cerebellar stem cells are quiescent. Data obtained by in vivo retrovirus injection indicate that stem cells do not produce neurons and astrocytes in adult mouse cerebellum. Instead, some cells labeled by retrovirus are Iba1{sup +} microglia. These results indicate that very few stem cells exist in adult mouse cerebellum, and none of these stem cells contribute to neurogenesis and astrogenesis under physiological condition.

  10. Cerebellar stem cells do not produce neurons and astrocytes in adult mouse

    International Nuclear Information System (INIS)

    Highlights: • No new neurons and astrocytes are generated in adult mouse cerebellum. • Very few mash1+ or nestin+ stem cells exist, and most of them are quiescent. • Cell proliferation rate is diversified among cerebellar regions and decreases over time. - Abstract: Although previous studies implied that cerebellar stem cells exist in some adult mammals, little is known about whether these stem cells can produce new neurons and astrocytes. In this study by bromodeoxyuridine (BrdU) intraperitoneal (i.p.) injection, we found that there are abundant BrdU+ cells in adult mouse cerebellum, and their quantity and density decreases significantly over time. We also found cell proliferation rate is diversified in different cerebellar regions. Among these BrdU+ cells, very few are mash1+ or nestin+ stem cells, and the vast majority of cerebellar stem cells are quiescent. Data obtained by in vivo retrovirus injection indicate that stem cells do not produce neurons and astrocytes in adult mouse cerebellum. Instead, some cells labeled by retrovirus are Iba1+ microglia. These results indicate that very few stem cells exist in adult mouse cerebellum, and none of these stem cells contribute to neurogenesis and astrogenesis under physiological condition

  11. Low in situ expression of antioxidative enzymes in rat cerebellar granular cells susceptible to methylmercury.

    Science.gov (United States)

    Fujimura, M; Usuki, F

    2014-01-01

    Methylmercury (MeHg), an environmental neurotoxicant, induces site-specific toxicity in the brain. Although oxidative stress has been demonstrated with MeHg toxicity, the site-specific toxicity is not completely understood. Among the cerebellar neurons, cerebellar granule cells (CGCs) appear vulnerable to MeHg, whereas Purkinje cells and molecular layer neurons are resistant. Here, we use a MeHg-intoxicated rat model to investigate these cerebellar neurons for the different causes of susceptibility to MeHg. Rats were exposed to 20 ppm MeHg for 4 weeks and subsequently exhibited neuropathological changes in the cerebellum that were similar to those observed in humans. We first isolated the three cerebellar neuron types using a microdissection system and then performed real-time PCR analyses for antioxidative enzymes. We observed that expression of manganese-superoxide dismutase (Mn-SOD), glutathione peroxidase 1 (GPx1), and thioredoxin reductase 1 (TRxR1) was significantly higher in Purkinje cells and molecular layer neurons than in CGCs. Finally, we performed immunohistochemical analyses on the cerebellum. Immunohistochemistry showed increased expression of Mn-SOD, GPx1, and TRxR1 in Purkinje cells and molecular layer neurons, which was coincident with the mRNA expression patterns. Considering Mn-SOD, GPx1, and TRxR1 are critical for protecting cells against MeHg intoxication, the results indicate that low expression of these antioxidative enzymes increases CGCs vulnerability to MeHg toxicity.

  12. MAM-2201, a synthetic cannabinoid drug of abuse, suppresses the synaptic input to cerebellar Purkinje cells via activation of presynaptic CB1 receptors.

    Science.gov (United States)

    Irie, Tomohiko; Kikura-Hanajiri, Ruri; Usami, Makoto; Uchiyama, Nahoko; Goda, Yukihiro; Sekino, Yuko

    2015-08-01

    Herbal products containing synthetic cannabinoids-initially sold as legal alternatives to marijuana-have become major drugs of abuse. Among the synthetic cannabinoids, [1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)-methanone (MAM-2201) has been recently detected in herbal products and has psychoactive and intoxicating effects in humans, suggesting that MAM-2201 alters brain function. Nevertheless, the pharmacological actions of MAM-2201 on cannabinoid receptor type 1 (CB1R) and neuronal functions have not been elucidated. We found that MAM-2201 acted as an agonist of human CB1Rs expressed in AtT-20 cells. In whole-cell patch-clamp recordings made from Purkinje cells (PCs) in slice preparations of the mouse cerebellum, we also found that MAM-2201 inhibited glutamate release at parallel fiber-PC synapses via activation of presynaptic CB1Rs. MAM-2201 inhibited neurotransmitter release with an inhibitory concentration 50% of 0.36 μM. MAM-2201 caused greater inhibition of neurotransmitter release than Δ(9)-tetrahydrocannabinol within the range of 0.1-30 μM and JWH-018, one of the most popular and potent synthetic cannabinoids detected in the herbal products, within the range of 0.03-3 μM. MAM-2201 caused a concentration-dependent suppression of GABA release onto PCs. Furthermore, MAM-2201 induced suppression of glutamate release at climbing fiber-PC synapses, leading to reduced dendritic Ca(2+) transients in PCs. These results suggest that MAM-2201 is likely to suppress neurotransmitter release at CB1R-expressing synapses in humans. The reduction of neurotransmitter release from CB1R-containing synapses could contribute to some of the symptoms of synthetic cannabinoid intoxication including impairments in cerebellum-dependent motor coordination and motor learning. PMID:25747605

  13. Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease

    Science.gov (United States)

    Chrysostomou, Alexia; Grady, John P.; Laude, Alex; Taylor, Robert W.; Turnbull, Doug M.

    2015-01-01

    Aims Cerebellar ataxia is common in patients with mitochondrial disease, and despite previous neuropathological investigations demonstrating vulnerability of the olivocerebellar pathway in patients with mitochondrial disease, the exact neurodegenerative mechanisms are still not clear. We use quantitative quadruple immunofluorescence to enable precise quantification of mitochondrial respiratory chain protein expression in Purkinje cell bodies and their synaptic terminals in the dentate nucleus. Methods We investigated NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 protein expression in 12 clinically and genetically defined patients with mitochondrial disease and ataxia and 10 age‐matched controls. Molecular genetic analysis was performed to determine heteroplasmy levels of mutated mitochondrial DNA in Purkinje cell bodies and inhibitory synapses. Results Our data reveal that complex I deficiency is present in both Purkinje cell bodies and their inhibitory synapses which surround dentate nucleus neurons. Inhibitory synapses are fewer and enlarged in patients which could represent a compensatory mechanism. Mitochondrial DNA heteroplasmy demonstrated similarly high levels of mutated mitochondrial DNA in cell bodies and synapses. Conclusions This is the first study to use a validated quantitative immunofluorescence technique to determine complex I expression in neurons and presynaptic terminals, evaluating the distribution of respiratory chain deficiencies and assessing the degree of morphological abnormalities affecting synapses. Respiratory chain deficiencies detected in Purkinje cell bodies and their synapses and structural synaptic changes are likely to contribute to altered cerebellar circuitry and progression of ataxia. PMID:26337858

  14. Electrophysiological evidence for glial-subtype glutamate transporter functional expression in rat cerebellar granule neurons

    Directory of Open Access Journals (Sweden)

    Mafra R.A.

    2003-01-01

    Full Text Available A glutamate-sensitive inward current (Iglu is described in rat cerebellar granule neurons and related to a glutamate transport mechanism. We examined the features of Iglu using the patch-clamp technique. In steady-state conditions the Iglu measured 8.14 ± 1.9 pA. Iglu was identified as a voltage-dependent inward current showing a strong rectification at positive potentials. L-Glutamate activated the inward current in a dose-dependent manner, with a half-maximal effect at about 18 µM and a maximum increase of 51.2 ± 4.4%. The inward current was blocked by the presence of dihydrokainate (0.5 mM, shown by others to readily block the GLT1 isoform. We thus speculate that Iglu could be attributed to the presence of a native glutamate transporter in cerebellar granule neurons.

  15. The postnatal development of cerebellar Purkinje cells in the Gottingen minipig estimated with a new stereological sampling technique--the vertical bar fractionator

    DEFF Research Database (Denmark)

    Jelsing, Jacob; Gundersen, Hans Jørgen Gottlieb; Nielsen, Rune;

    2006-01-01

    minipigs. The total number of Purkinje cells ranged from 1.83 x 10(6) in the neonate to 2.82 x 10(6) in the adult Gottingen minipig. The number-weighted mean perikaryon volume of Purkinje cells increased concurrently from around 6,800 microm(3) in the neonate to 17,600 microm(3) in the adult. The study...... cells described hitherto from mammalian cerebella. The vertical fractionator is a new sampling technique, which allows the combination of a fractionator design on vertical bar sections excluding exhaustive sampling and bias from artificial edges. By design, the sections are perfect stereological...

  16. Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons

    DEFF Research Database (Denmark)

    Li, Shizhong; Christensen, Claus; Køhler, Lene B;

    2009-01-01

    Fibroblast growth factor receptor (FGFR) signaling is pivotal in the regulation of neurogenesis, neuronal differentiation and survival, and synaptic plasticity both during development and in adulthood. In order to develop low molecular weight agonists of FGFR, seven peptides, termed hexafins...... phosphorylation, indicating that hexafins act as partial agonists. Hexafin2, 3, 8, 10, and 17 (but not 1 or 9) induced neurite outgrowth from cerebellar granule neurons (CGNs), an effect that was abolished by two inhibitors of FGFR, SU5402 and inositol hexaphosphate (IP6) and a diacylglycerol lipase inhibitor...

  17. Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth

    Science.gov (United States)

    Haldipur, Parthiv; Gillies, Gwendolyn S; Janson, Olivia K; Chizhikov, Victor V; Mithal, Divakar S; Miller, Richard J; Millen, Kathleen J

    2014-01-01

    Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans. DOI: http://dx.doi.org/10.7554/eLife.03962.001 PMID:25513817

  18. Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer's disease rats.

    Science.gov (United States)

    Lee, Jae-Min; Shin, Mal-Soon; Ji, Eun-Sang; Kim, Tae-Woon; Cho, Han-Sam; Kim, Chang-Ju; Jang, Myung-Soo; Kim, Tae-Wook; Kim, Bo-Kyun; Kim, Dong-Hee

    2014-10-01

    Alzheimer's disease (AD) is a most common age-related neurodegenerative disease. AD is characterized by a progressive loss of neurons causing cognitive dysfunction. The cerebellum is closely associated with integration of movement, including motor coordination, control, and equilibrium. In the present study, we evaluated the effect of tread-mill exercise on the survival of Purkinje neurons in relation with reactive astrocyte in the cerebellum using Aβ25-35-induced AD rats. AD was induced by a bilateral intracerebroventricular (ICV) injection of Aβ25-35. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks, starting 2 days after Aβ25-35 injection. In the present results, ICV injection of Aβ25-35 deteriorated motor coordination and balance. The number of calbindin-positive cells in the cerebellar vermis was decreased and glial fibrillary acidic protein (GFAP) expression in the cerebellar vermis was increased in the Aβ25-35-induced AD rats. Treadmill exercise improved motor coordination and balance. Treadmill exercise increased the number of Purkinje neurons and suppressed GFAP expression in the cerebellar vermis. The present study demonstrated that treadmill exercises alleviated dysfunction of motor coordination and balance by reduction of Purkinje cell loss through suppressing reactive astrocytes in the cerebellum of AD rats. The present study provides the possibility that treadmill exercise might be an important therapeutic strategy for the symptom improvement of AD patients. PMID:25426461

  19. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3

    NARCIS (Netherlands)

    Verbeek, D S; van de Warrenburg, B P; Wesseling, P; Pearson, P L; Kremer, H P; Sinke, R J

    2004-01-01

    We report upon a Dutch autosomal dominant cerebellar ataxia (ADCA) family, clinically characterized by a late-onset (>40 years), slowly progressive, isolated spinocerebellar ataxia (SCA). Neuropathological examination in one affected subject showed neuronal loss in the Purkinje cell layer, dentate n

  20. Purkinje cell maturation participates in the control of oligodendrocyte differentiation: role of sonic hedgehog and vitronectin.

    Science.gov (United States)

    Bouslama-Oueghlani, Lamia; Wehrlé, Rosine; Doulazmi, Mohamed; Chen, Xiao Ru; Jaudon, Fanny; Lemaigre-Dubreuil, Yolande; Rivals, Isabelle; Sotelo, Constantino; Dusart, Isabelle

    2012-01-01

    Oligodendrocyte differentiation is temporally regulated during development by multiple factors. Here, we investigated whether the timing of oligodendrocyte differentiation might be controlled by neuronal differentiation in cerebellar organotypic cultures. In these cultures, the slices taken from newborn mice show very few oligodendrocytes during the first week of culture (immature slices) whereas their number increases importantly during the second week (mature slices). First, we showed that mature cerebellar slices or their conditioned media stimulated oligodendrocyte differentiation in immature slices thus demonstrating the existence of diffusible factors controlling oligodendrocyte differentiation. Using conditioned media from different models of slice culture in which the number of Purkinje cells varies drastically, we showed that the effects of these differentiating factors were proportional to the number of Purkinje cells. To identify these diffusible factors, we first performed a transcriptome analysis with an Affymetrix array for cerebellar cortex and then real-time quantitative PCR on mRNAs extracted from fluorescent flow cytometry sorted (FACS) Purkinje cells of L7-GFP transgenic mice at different ages. These analyses revealed that during postnatal maturation, Purkinje cells down-regulate Sonic Hedgehog and up-regulate vitronectin. Then, we showed that Sonic Hedgehog stimulates the proliferation of oligodendrocyte precursor cells and inhibits their differentiation. In contrast, vitronectin stimulates oligodendrocyte differentiation, whereas its inhibition with blocking antibodies abolishes the conditioned media effects. Altogether, these results suggest that Purkinje cells participate in controlling the timing of oligodendrocyte differentiation in the cerebellum through the developmentally regulated expression of diffusible molecules such as Sonic Hedgehog and vitronectin. PMID:23155445

  1. Purkinje cell maturation participates in the control of oligodendrocyte differentiation: role of sonic hedgehog and vitronectin.

    Directory of Open Access Journals (Sweden)

    Lamia Bouslama-Oueghlani

    Full Text Available Oligodendrocyte differentiation is temporally regulated during development by multiple factors. Here, we investigated whether the timing of oligodendrocyte differentiation might be controlled by neuronal differentiation in cerebellar organotypic cultures. In these cultures, the slices taken from newborn mice show very few oligodendrocytes during the first week of culture (immature slices whereas their number increases importantly during the second week (mature slices. First, we showed that mature cerebellar slices or their conditioned media stimulated oligodendrocyte differentiation in immature slices thus demonstrating the existence of diffusible factors controlling oligodendrocyte differentiation. Using conditioned media from different models of slice culture in which the number of Purkinje cells varies drastically, we showed that the effects of these differentiating factors were proportional to the number of Purkinje cells. To identify these diffusible factors, we first performed a transcriptome analysis with an Affymetrix array for cerebellar cortex and then real-time quantitative PCR on mRNAs extracted from fluorescent flow cytometry sorted (FACS Purkinje cells of L7-GFP transgenic mice at different ages. These analyses revealed that during postnatal maturation, Purkinje cells down-regulate Sonic Hedgehog and up-regulate vitronectin. Then, we showed that Sonic Hedgehog stimulates the proliferation of oligodendrocyte precursor cells and inhibits their differentiation. In contrast, vitronectin stimulates oligodendrocyte differentiation, whereas its inhibition with blocking antibodies abolishes the conditioned media effects. Altogether, these results suggest that Purkinje cells participate in controlling the timing of oligodendrocyte differentiation in the cerebellum through the developmentally regulated expression of diffusible molecules such as Sonic Hedgehog and vitronectin.

  2. Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons

    OpenAIRE

    Molineux, Michael L.; McRory, John E.; McKay, Bruce E.; Hamid, Jawed; Mehaffey, W. Hamish; Rehak, Renata; Snutch, Terrance P; Gerald W Zamponi; Turner, Ray W

    2006-01-01

    T-type calcium channels are thought to transform neuronal output to a burst mode by generating low voltage-activated (LVA) calcium currents and rebound burst discharge. In this study we assess the expression pattern of the three different T-type channel isoforms (Cav3.1, Cav3.2, and Cav3.3) in cerebellar neurons and focus on their potential role in generating LVA spikes and rebound discharge in deep cerebellar nuclear (DCN) neurons. We detected expression of one or more Cav3 channel isoforms ...

  3. Increased excitability and altered action potential waveform in cerebellar granule neurons of the Ts65Dn mouse model of Down syndrome.

    Science.gov (United States)

    Usowicz, Maria M; Garden, Claire L P

    2012-07-17

    Down syndrome (DS) is characterized by intellectual disability and impaired motor control. Lack of coordinated movement, poor balance, and unclear speech imply dysfunction of the cerebellum, which is known to be reduced in volume in DS. The principal cause of the smaller cerebellum is a diminished number of granule cells (GCs). These neurons form the 'input layer' of the cerebellar cortex, where sensorimotor information carried by incoming mossy fibers is transformed before it is conveyed to Purkinje cells and inhibitory interneurons. However, it is not known how processing of this information is affected in the hypogranular cerebellum that characterizes DS. Here we explore the possibility that the electrical properties of the surviving GCs are changed. We find that in the Ts65Dn mouse model of DS, GCs have a higher input resistance at voltages approaching the threshold for firing, which causes them to be more excitable. In addition, they fire narrower and larger amplitude action potentials. These subtly modified electrical properties may result in atypical transfer of information at the input layer of the cerebellum.

  4. An increased expression of Ca(2+) channel alpha(1A) subunit immunoreactivity in deep cerebellar neurons of rolling mouse Nagoya.

    Science.gov (United States)

    Sawada, K; Sakata-Haga, H; Ando, M; Takeda, N; Fukui, Y

    2001-12-01

    Rolling mouse Nagoya (RMN) is an ataxic mutant and carries a mutation in the gene coding for the alpha(1A) subunit of the P/Q-type Ca(2+) channel. We examined the immunohistochemical expression of the alpha(1A) subunit in deep cerebellar nuclei of RMN. The antibody used recognized residues 865-883 of the mouse alpha(1A) subunit not overlapping the altered sequences in RMN. In RMN, many neurons exhibited definite alpha(1A) subunit-staining in the medial nucleus, interposed nucleus, and lateral nucleus of deep cerebellar nuclei. The number of positive neurons in these nuclei was significantly higher in RMN than in controls. Increased expression of the alpha(1A) subunit in deep cerebellar neurons might compensate for the altered function of the P/Q-type Ca(2+) channel of RMN.

  5. Developmental disorders of the brain can be caused by PCBs; low doses of hydroxy-PCBs disrupt thyroid hormone-dependent dendrite formation from Purkinje neurons in culture

    Energy Technology Data Exchange (ETDEWEB)

    Kuroda, Y.; Kimura-Kuroda, J. [Tokyo Metropol. Inst. for Neuroscience, Tokyo (Japan); Nagata, I. [CREST/ JST, Tokyo (Japan)

    2004-09-15

    Exposure to some environmental chemicals during the perinatal period causes developmental disorders of the brain. Cognitive impairment and hyperactivity in infants were reported in Taiwan, known as Yu-cheng incidents caused by the accidental contamination of polychlorinated biphenyls (PCBs). Together with recent experimental data, Kuroda proposes a hypothesis that spatio-temporal disruptions of developing neuronal circuits by PCB exposure can cause the comobidity of learning disorders (LD), attention deficit hyperactivity disorder (ADHD) and autsm with the co-exposure to other environmental chemicals. PCBs and hydroxylated PCBs (OH-PCBs) have similar chemical structures to thyroid hormones (TH), thyroxine (T4) and triiodothyronine (T3). TH deficiency in the perinatal period causes cretinism children with severe cognitive and mental retardation. In primate model, Rice demonstrates that postnatal exposure to PCBs can dramatically influence later behavioral function. Epidemiological studies also indicate the possible developmental neurotoxicity of PCBs accumulated in human bodies. However, the precise underlying mechanisms and which types of PCB or OH-PCB with such effects have yet to be elucidated. It is important to establish a simple, reproducible, and sensitive in vitro assay for determining the effects of PCBs and OH-PCBs on the development of the central nervous system. Recently Iwasaki et al. established a reporter assay system and disclosed that low doses of PCBs potentially interfere TH-dependent gene expressions. This is the first demonstration that PCBs and OH-PCBs directly affect TH-receptor (TR)-mediated gene expressions crucial to the brain development, through unique mechanism. We also have demonstrated TH-dependent development of Purkinje neurons in vitro using a serum-free chemically defined medium. The degree of dendritic development of Purkinje cells is TH dose-dependent and exhibits high sensitivity in the pM order. Therefore, in the present study

  6. Development of the cerebellar cortex in the mouse

    Institute of Scientific and Technical Information of China (English)

    Xiangshu Cheng; Jin Du; Dongming Yu; Qiying Jiang; Yanqiu Hu; Lei Wang; Mingshan Li; Jinbo Deng

    2011-01-01

    The cerebellum is a highly conserved structure in the central nervous system of vertebrates, and is involved in the coordination of voluntary motor behavior. Supporting this function, the cerebellar cortex presents a layered structure which requires precise spatial and temporal coordination of proliferation, migration, differentiation, and apoptosis events. The formation of the layered structure in the developing cerebellum remains unclear. The present study investigated the development of the cerebellar cortex. The results demonstrate that the primordium of the cerebellum comprises the ependymal, mantle, and marginal layers at embryonic day 12 (E12). Subsequently, the laminated cerebellar cortex undergoes cell proliferation, differentiation, and migration, and at about postnatal day 0 (P0), the cerebellar cortex presents an external granular layer, a molecular layer, a Purkinje layer, and an internal granular layer. The external granular layer is thickest at P6/7 and disappears at P20. From P0 to P30, the internal granular cells and the Purkinje cells gradually differentiate and develop until maturity. Apoptotic neurons are evident in the layered structure in the developing cerebellar cortex. The external granular layer disappears gradually because of cell migration and apoptosis. The cells of the other layers primarily undergo differentiation, development, and apoptosis.

  7. IgG from Amyotrophic Lateral Sclerosis Patients Increases Current Through P-Type Calcium Channels in Mammalian Cerebellar Purkinje Cells and in Isolated Channel Protein in Lipid Bilayer

    Science.gov (United States)

    Llinas, R.; Sugimori, M.; Cherksey, B. D.; Smith, R. Glenn; Delbono, O.; Stefani, E.; Appel, S.

    1993-12-01

    The effect of the IgG from amyotrophic lateral sclerosis (ALS) patients was tested on the voltage-dependent barium currents (IBa) in mammalian dissociated Purkinje cells and in isolated P-type calcium channels in lipid bilayers. Whole cell clamp of Purkinje cells demonstrates that ALS IgG increases the amplitude of IBa without modifying their voltage kinetics. This increased IBa could be blocked by a purified nonpeptide toxin from Agelenopsis aperta venom (purified funnel-web spider toxin) or by a synthetic polyamine analog (synthetic funnel-web spider toxin) and by a peptide toxin from the same spider venom, ω-Aga-IVA. Similar results were obtained on single-channel recordings from purified P channel protein. The addition of ALS IgG increased single-channel IBa open time without affecting slope conductance. The results described above were not seen with normal human IgG nor with boiled ALS IgG. It is concluded that ALS IgG enhances inward current through P-type calcium channels. Since P-type Ca2+ channels are present in motoneuron axon terminals, we propose that the enhanced calcium current triggered by ALS IgG may contribute to neuronal damage in ALS.

  8. Conditional induction of Math1 specifies embryonic stem cells to cerebellar granule neuron lineage and promotes differentiation into mature granule neurons.

    Science.gov (United States)

    Srivastava, Rupali; Kumar, Manoj; Peineau, Stéphane; Csaba, Zsolt; Mani, Shyamala; Gressens, Pierre; El Ghouzzi, Vincent

    2013-04-01

    Directing differentiation of embryonic stem cells (ESCs) to specific neuronal subtype is critical for modeling disease pathology in vitro. An attractive means of action would be to combine regulatory differentiation factors and extrinsic inductive signals added to the culture medium. In this study, we have generated mature cerebellar granule neurons by combining a temporally controlled transient expression of Math1, a master gene in granule neuron differentiation, with inductive extrinsic factors involved in cerebellar development. Using a Tetracyclin-On transactivation system, we overexpressed Math1 at various stages of ESCs differentiation and found that the yield of progenitors was considerably increased when Math1 was induced during embryonic body stage. Math1 triggered expression of Mbh1 and Mbh2, two target genes directly involved in granule neuron precursor formation and strong expression of early cerebellar territory markers En1 and NeuroD1. Three weeks after induction, we observed a decrease in the number of glial cells and an increase in that of neurons albeit still immature. Combining Math1 induction with extrinsic factors specifically increased the number of neurons that expressed Pde1c, Zic1, and GABAα6R characteristic of mature granule neurons, formed "T-shaped" axons typical of granule neurons, and generated synaptic contacts and action potentials in vitro. Finally, in vivo implantation of Math1-induced progenitors into young adult mice resulted in cell migration and settling of newly generated neurons in the cerebellum. These results show that conditional induction of Math1 drives ESCs toward the cerebellar fate and indicate that acting on both intrinsic and extrinsic factors is a powerful means to modulate ESCs differentiation and maturation into a specific neuronal lineage.

  9. Paeoniflorin inhibits functional responses of rat cerebellar Purkinje cells to acute hypoxia insult%芍药苷抑制大鼠小脑浦肯野细胞对急性缺氧的功能反应

    Institute of Scientific and Technical Information of China (English)

    任颖鸽; 谭晓丽; 陈静; 张静; 杜永平; 张月萍

    2015-01-01

    [ ABSTRACT] AIM:To investigate the effects of paeoniflorin ( Pae) on the functional responses induced by acute hypoxic insult in the rat cerebellar Purkinje cells ( PCs) .METHODS:The whole-cell patch clamp was used for the intra-cellular recording of PCs in the rat cerebellar slices to evaluate the changes of membrane potential, the excitability of PCs, and the parallel fibre ( PF)-PC excitatory postsynaptic currents ( EPSCs) upon acute hypoxic insult alone or with the pre-sence of Pae.RESULTS:PCs showed an initial hyperpolarization followed by brief depolarization and long lasting post-hy-poxia hyperpolarization after hypoxia exposure.Pae completely blocked hypoxia-induced hyperpolarization and decreased the amplitude and the duration of hypoxic depolarization.Hypoxia up-regulated the excitability of rat PCs.Pae didn’t show any significant effect on the hypoxia-induced hyperexcitability in PCs.Acute hypoxia induced long-term depression ( LTD) in rat cerebellar PF-PC EPSCs, and Pae partially reversed hypoxia-induced depression in PF-PC EPSCs.CONCLUSION:Pae significantly suppresses hypoxia-induced responses in rat PCs and probably increases the tolerance of rat PCs to acute hypoxia.%目的:研究芍药苷(paeoniflorin,Pae)对大鼠小脑浦肯野细胞(Purkinje cells,PCs)急性缺氧电生理反应的影响。方法:采用全细胞膜片钳记录法,记录大鼠小脑PCs膜电位、兴奋性和平行纤维( parallel fibre,PF)-PC兴奋性突触后电流(excitatory postsynaptic currents,EPSCs),观察急性缺氧和芍药苷对上述电生理功能的影响。结果:缺氧后PCs首先表现为短暂的超极化,继之以短暂的去极化和持续超极化,芍药苷完全阻断了PCs的缺氧性超极化,并使PCs缺氧性去极化的幅度减小,持续时间缩短;缺氧上调了PCs兴奋性,芍药苷对缺氧引起的PCs的高兴奋性无显著影响;急性缺氧引起了PF-PC EPSCs的长时程抑制( long

  10. Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

    Science.gov (United States)

    Dar, M Saeed

    2015-08-01

    The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.

  11. Parallel fiber to Purkinje cell synaptic impairment in a mouse model of spinocerebellar ataxia type 27

    Directory of Open Access Journals (Sweden)

    Filippo eTempia

    2015-06-01

    Full Text Available Genetically inherited mutations in the fibroblast growth factor 14 (FGF14 gene lead to spinocerebellar ataxia type 27 (SCA27, an autosomal dominant disorder characterized by severe heterogeneous motor and cognitive impairments. Consistently, genetic deletion of Fgf14 in Fgf14-/- mice recapitulates salient features of the SCA27 human disease. In vitro molecular studies in cultured neurons indicate that the FGF14F145S SCA27 allele acts as a dominant negative mutant suppressing the FGF14 wild type function and resulting in inhibition of voltage-gated Na+ and Ca2+ channels. To gain insights in the cerebellar deficits in the animal model of the human disease, we applied whole-cell voltage-clamp in the acute cerebellar slice preparation to examine the properties of parallel fibers (PF to Purkinje neuron synapses in Fgf14-/- mice and wild type littermates. We found that the AMPA receptor-mediated excitatory postsynaptic currents evoked by PF stimulation (PF-EPSCs were significantly reduced in Fgf14-/- animals, while short-term plasticity, measured as paired-pulse facilitation (PPF, was enhanced. Measuring Sr2+-induced release of quanta from stimulated synapses, we found that the size of the PF-EPSCs was unchanged, ruling out a postsynaptic deficit. This phenotype was corroborated by decreased expression of VGLUT1, a specific presynaptic marker at PF-Purkinje neuron synapses. We next examined the mGluR1 receptor-induced response (mGluR1-EPSC that under normal conditions requires a gradual build-up of glutamate concentration in the synaptic cleft, and found no changes in these responses in Fgf14-/- mice. These results provide evidence of a critical role of FGF14 in maintaining presynaptic function at PF-Purkinje neuron synapses highlighting critical target mechanisms to recapitulate the complexity of the SCA27 disease.

  12. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit

    Directory of Open Access Journals (Sweden)

    Lisa eMapelli

    2015-05-01

    Full Text Available The way long-term potentiation (LTP and depression (LTD are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network , in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei and correspondingly regulate the function of their three main neurons: granule cells (GrCs, Purkinje cells (PCs and deep cerebellar nuclear (DCN cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  13. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

    Science.gov (United States)

    Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

    2015-01-01

    The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  14. Modulation of p53 and met expression by Krüppel-like factor 8 regulates zebrafish cerebellar development.

    Science.gov (United States)

    Tsai, Ming-Yuan; Lu, Yu-Fen; Liu, Yu-Hsiu; Lien, Huang-Wei; Huang, Chang-Jen; Wu, Jen-Leih; Hwang, Sheng-Ping L

    2015-09-01

    Krüppel-like factor 8 (Klf8) is a zinc-finger transcription factor implicated in cell proliferation, and cancer cell survival and invasion; however, little is known about its role in normal embryonic development. Here, we show that Klf8 is required for normal cerebellar development in zebrafish embryos. Morpholino knockdown of klf8 resulted in abnormal cerebellar primordium morphology and the induction of p53 in the brain region at 24 hours post-fertilization (hpf). Both p53-dependent reduction of cell proliferation and augmentation of apoptosis were observed in the cerebellar anlage of 24 hpf-klf8 morphants. In klf8 morphants, expression of ptf1a in the ventricular zone was decreased from 48 to 72 hpf; on the other hand, expression of atohla in the upper rhombic lip was unaffected. Consistent with this finding, Purkinje cell development was perturbed and granule cell number was reduced in 72 hpf-klf8 morphants; co-injection of p53 MO(sp) or klf8 mRNA substantially rescued development of cerebellar Purkinje cells in klf8 morphants. Hepatocyte growth factor/Met signaling is known to regulate cerebellar development in zebrafish and mouse. We observed decreased met expression in the tectum and rhombomere 1 of 24 hpf-klf8 morphants, which was largely rescued by co-injection with klf8 mRNA. Moreover, co-injection of met mRNA substantially rescued formation of Purkinje cells in klf8 morphants at 72 hpf. Together, these results demonstrate that Klf8 modulates expression of p53 and met to maintain ptf1a-expressing neuronal progenitors, which are required for the appropriate development of cerebellar Purkinje and granule cells in zebrafish embryos.

  15. Role of glutamate receptors in tetrabrominated diphenyl ether (BDE-47) neurotoxicity in mouse cerebellar granule neurons.

    Science.gov (United States)

    Costa, Lucio G; Tagliaferri, Sara; Roqué, Pamela J; Pellacani, Claudia

    2016-01-22

    The polybrominated diphenyl ether (PBDE) flame retardants are developmental neurotoxicants, as evidenced by numerous in vitro, animal and human studies. PBDEs can alter the homeostasis of thyroid hormone and directly interact with brain cells. Induction of oxidative stress, leading to DNA damage and apoptotic cell death is a prominent mechanism of PBDE neurotoxicity, though other mechanisms have also been suggested. In the present study we investigated the potential role played by glutamate receptors in the in vitro neurotoxicity of the tetrabromodiphenyl ether BDE-47, one of the most abundant PBDE congeners. Toxicity of BDE-47 in mouse cerebellar neurons was diminished by antagonists of glutamate ionotropic receptors, but not by antagonists of glutamate metabotropic receptors. Antagonists of NMDA and AMPA/Kainate receptors also inhibited BDE-47-induced oxidative stress and increases in intracellular calcium. The calcium chelator BAPTA-AM also inhibited BDE-47 cytotoxicity and oxidative stress. BDE-47 caused a rapid increase of extracellular glutamate levels, which was not antagonized by any of the compounds tested. The results suggest that BDE-47, by still unknown mechanisms, increases extracellular glutamate which in turn activates ionotropic glutamate receptors leading to increased calcium levels, oxidative stress, and ultimately cell death. PMID:26640238

  16. A computational study of synaptic mechanisms of partial memory transfer in cerebellar vestibulo-ocular-reflex learning.

    Science.gov (United States)

    Masuda, Naoki; Amari, Shun-ichi

    2008-04-01

    There is a debate regarding whether motor memory is stored in the cerebellar cortex, or the cerebellar nuclei, or both. Memory may be acquired in the cortex and then be transferred to the cerebellar nuclei. Based on a dynamical system modeling with a minimal set of variables, we theoretically investigated possible mechanisms of memory transfer and consolidation in the context of vestibulo-ocular reflex learning. We tested different plasticity rules for synapses in the cerebellar nuclei and took robustness of behavior against parameter variation as the criterion of plausibility of a model variant. In the most plausible scenarios, mossy-fiber nucleus-neuron synapses or Purkinje-cell nucleus-neuron synapses are plastic on a slow time scale and store permanent memory, whose content is passed from the cerebellar cortex storing transient memory. In these scenarios, synaptic strengths are potentiated when the mossy-fiber afferents to the nuclei are active during a pause in Purkinje-cell activities. Furthermore, assuming that mossy fibers create a limited variety of signals compared to parallel fibers, our model shows partial memory transfer from the cortex to the nuclei.

  17. Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum

    OpenAIRE

    Piochon, Claire; Levenes, Carole; Ohtsuki, Gen; Hansel, Christian

    2010-01-01

    textabstractA classic view in cerebellar physiology holds that Purkinje cells do not express functional NMDA receptors and that, therefore, postsynaptic NMDA receptors are not involved in the induction of long-term depression (LTD) at parallel fiber (PF) to Purkinje cell synapses. Recently, it has been demonstrated that functional NMDA receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in mice, reaching full expression levels at ∼2 months after birth. He...

  18. Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum

    NARCIS (Netherlands)

    C. Piochon (Claire); C. Levenes (Carole); G. Ohtsuki (Gen); C.R.W. Hansel (Christian)

    2010-01-01

    textabstractA classic view in cerebellar physiology holds that Purkinje cells do not express functional NMDA receptors and that, therefore, postsynaptic NMDA receptors are not involved in the induction of long-term depression (LTD) at parallel fiber (PF) to Purkinje cell synapses. Recently, it has b

  19. Age-related changes of structures in cerebellar cortex of cat

    Indian Academy of Sciences (India)

    Changzheng Zhang; Tianmiao Hua; Zaiman Zhu; Xun Luo

    2006-03-01

    We studied the structures of the cerebellar cortex of young adult and old cats for age-related changes, which were statistically analysed. Nissl staining was used to visualize the cortical neurons. The immunohistochemical method was used to display glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes and neurofilament-immunoreactive (NF-IR) neurons. Under the microscope, the thickness of the cerebellar cortex was measured; and the density of neurons in all the layers as well as that of GFAP-IR cells in the granular layer was analysed. Compared with young adult cats, the thickness of the molecular layer and total cerebellar cortex was significantly decreased in old cats, and that of the granular layer increased. The density of neurons in each layer was significantly lower in old cats than in young adult ones. Astrocytes in old cats were significantly denser than in young adult ones, and accompanied by evident hypertrophy of the cell bodies and enhanced immunoreaction of GFAP substance. Purkinje cells (PCs) in old cats showed much fewer NF-IR dendrites than those in young adults. The above findings indicate a loss of neurons and decrease in the number of dendrites of the PCs in the aged cerebellar cortex, which might underlie the functional decline of afferent efficacy and information integration in the senescent cerebellum. An age-dependent enhancement of activity of the astrocytes may exert a protective effect on neurons in the aged cerebellum.

  20. Long lasting cerebellar alterations after perinatal asphyxia in rats.

    Science.gov (United States)

    Campanille, Verónica; Saraceno, G Ezequiel; Rivière, Stéphanie; Logica, Tamara; Kölliker, Rodolfo; Capani, Francisco; Castilla, Rocío

    2015-07-01

    The developing brain may be particularly vulnerable to injury before, at and after birth. Among possible insults, hypoxia suffered as a consequence of perinatal asphyxia (PA) exhibits the highest incidence levels and the cerebellar circuitry appears to be particularly susceptible, as the cellular makeup and the quantity of inputs change quickly during days and weeks following birth. In this work, we have used a murine model to induce severe global PA in rats at the time of birth. Short-term cerebellar alterations within this PA model have been previously reported but whether such alterations remain in adulthood has not been conclusively determined yet. For this reason, and given the crucial cerebellar role in determining connectivity patterns in the brain, the aim of our work is to unveil long-term cerebellum histomorphology following a PA insult. Morphological and cytological neuronal changes and glial reaction in the cerebellar cortex were analyzed at postnatal 120 (P120) following injury performed at birth. As compared to control, PA animals exhibited: (1) an increase in molecular and granular thickness, both presenting lower cellular density; (2) a disarrayed Purkinje cell layer presenting a higher number of anomalous calbindin-stained cells. (3) focal swelling and marked fragmentation of microtubule-associated protein 2 (MAP-2) in Purkinje cell dendrites and, (4) an increase in glial fibrillary acidic protein (GFAP) expression in Bergmann cells and the granular layer. In conclusion, we demonstrate that PA produces long-term damage in cellular histomorphology in rat cerebellar cortex which could be involved in the pathogenesis of cognitive deficits observed in both animals and humans.

  1. Long lasting cerebellar alterations after perinatal asphyxia in rats.

    Science.gov (United States)

    Campanille, Verónica; Saraceno, G Ezequiel; Rivière, Stéphanie; Logica, Tamara; Kölliker, Rodolfo; Capani, Francisco; Castilla, Rocío

    2015-07-01

    The developing brain may be particularly vulnerable to injury before, at and after birth. Among possible insults, hypoxia suffered as a consequence of perinatal asphyxia (PA) exhibits the highest incidence levels and the cerebellar circuitry appears to be particularly susceptible, as the cellular makeup and the quantity of inputs change quickly during days and weeks following birth. In this work, we have used a murine model to induce severe global PA in rats at the time of birth. Short-term cerebellar alterations within this PA model have been previously reported but whether such alterations remain in adulthood has not been conclusively determined yet. For this reason, and given the crucial cerebellar role in determining connectivity patterns in the brain, the aim of our work is to unveil long-term cerebellum histomorphology following a PA insult. Morphological and cytological neuronal changes and glial reaction in the cerebellar cortex were analyzed at postnatal 120 (P120) following injury performed at birth. As compared to control, PA animals exhibited: (1) an increase in molecular and granular thickness, both presenting lower cellular density; (2) a disarrayed Purkinje cell layer presenting a higher number of anomalous calbindin-stained cells. (3) focal swelling and marked fragmentation of microtubule-associated protein 2 (MAP-2) in Purkinje cell dendrites and, (4) an increase in glial fibrillary acidic protein (GFAP) expression in Bergmann cells and the granular layer. In conclusion, we demonstrate that PA produces long-term damage in cellular histomorphology in rat cerebellar cortex which could be involved in the pathogenesis of cognitive deficits observed in both animals and humans. PMID:26116983

  2. Reactive oxygen species are related to ionic fluxes and volume decrease in apoptotic cerebellar granule neurons: role of NOX enzymes.

    Science.gov (United States)

    Hernández-Enríquez, Berenice; Guemez-Gamboa, Alicia; Morán, Julio

    2011-05-01

    Reactive oxygen species (ROS) are produced early during apoptosis of cerebellar granule neurons induced by low potassium (K5) and staurosporine (Sts). In addition, K5 and Sts activate NADPH oxidases (NOX). Recently, we described that K5 and Sts induce apoptotic volume decrease (AVD) at a time when ROS generation and NOX activity occur. In the present study, we evaluated the relationship between ROS generation and ionic fluxes during AVD. Here, we showed that K5- and Sts-induced AVD was inhibited by antioxidants and that direct ROS production induced AVD. Moreover, NOX inhibitors eliminated AVD induced by both K5 and Sts. Sts, but not K5, failed to induce AVD in cerebellar granule neurons from NOX2 knockout mice. These findings suggest that K5- and Sts-induced AVD is largely mediated by ROS produced by NOX. On the other hand, we also found that the blockage of ionic fluxes involved in AVD inhibited both ROS generation and NOX activity. These findings suggest that ROS generation and NOX activity are involved in ionic fluxes activation, which in turn could maintain ROS generation by activating NOX, leading to a self-amplifying cycle.

  3. Estudo estereológico das células de Purkinje cerebelares submetidas à intoxicação alcoólica em ratos Wistar Stereologic study of the cerebellar Purkinje cells submitted to alcoholic intoxication in Wistar rats

    Directory of Open Access Journals (Sweden)

    Mara Ibis Rodrigues Apfel

    2002-06-01

    Full Text Available MOTIVO DO ESTUDO: Analisar o efeito do álcool sobre as células de Purkinje de ratos. MÉTODO: Ratos Wistar receberam oralmente soluções alcoólicas em diferentes concentrações 4%, 12% e 24%. Os animais foram sacrificados com 4, 8 e 12 semanas e os cerebelos foram clivados em cortes aleatórios e uniformemente isotrópicos e incluídos em parafina. Cortes de 6µm (H & E foram analisados por estereologia. RESULTADOS: As diferenças entre a densidade por área e densidade de superfície das células de Purkinje de todos os grupos experimentais (E e os respectivos controles (C foram significativas. Com 12 semanas, a densidade volumétrica da célula de Purkinje diminuiu entre os grupos C e E nas concentrações de 4% e 12%, mas não para a concentração de 24%, provavelmente devido a menor ingestão de líquido pelos animais. CONCLUSÃO: O álcool exerceu efeito tóxico sobre o corpo celular da célula de Purkinje nas três concentrações estudadas a partir de 4 semanas.BACKGROUND: to analyze the effect of the alcohol on the cells of Purkinje. METHOD: Wistar rats received alcoholic solutions orally in different concentrations 4%, 12% and 24%. The animals were sacrificed with 4, 8 and 12 weeks and the cerebella were randomly cut and embedded in paraffin. Sections of 6µm (H&E were stereologically analyzed. RESULTS: The differences among the density for area and density of surface of the cells of Purkinje of all of the experimental groups (E and the respective controls (C were significant. With 12 weeks the cell of Purkinje volume density decreased among the groups C and E in the concentrations of 4% and 12%, but not for the concentration of 24%, probably due to smaller liquid ingestion by the animals. CONCLUSION: The alcohol has toxic effect on the Purkinje cellular body in the three studied concentrations from 4 weeks.

  4. Contribution of plasma membrane Ca2+ ATPase to cerebellar synapse function

    Institute of Scientific and Technical Information of China (English)

    Helena; Huang; Raghavendra; Y; Nagaraja; Molly; L; Garside; Walther; Akemann; Thomas; Knpfel; Ruth; M; Empson

    2010-01-01

    The cerebellum expresses one of the highest levels of the plasma membrane Ca2+ATPase,isoform 2 in the mammalian brain.This highly efficient plasma membrane calcium transporter protein is enriched within the main output neurons of the cerebellar cortex;i.e. the Purkinje neurons(PNs) .Here we review recent evidence,including electrophysiological and calcium imaging approaches using the plasma membrane calcium ATPase 2(PMCA2) knockout mouse,to show that PMCA2 is critical for the physiological control of calcium at cerebellar synapses and cerebellar dependent behaviour.These studies have also revealed that deletionof PMCA2 throughout cerebellar development in the PMCA2 knockout mouse leads to permanent signalling and morphological alterations in the PN dendrites. Whilst these findings highlight the importance of PMCA2 during cerebellar synapse function and development,they also reveal some limitations in the use of the PMCA2 knockout mouse and the need for additional experimental approaches including cell-specific and reversible manipulation of PMCAs.

  5. Nicotine-like effects of the neonicotinoid insecticides acetamiprid and imidacloprid on cerebellar neurons from neonatal rats.

    Directory of Open Access Journals (Sweden)

    Junko Kimura-Kuroda

    Full Text Available BACKGROUND: Acetamiprid (ACE and imidacloprid (IMI belong to a new, widely used class of pesticide, the neonicotinoids. With similar chemical structures to nicotine, neonicotinoids also share agonist activity at nicotinic acetylcholine receptors (nAChRs. Although their toxicities against insects are well established, their precise effects on mammalian nAChRs remain to be elucidated. Because of the importance of nAChRs for mammalian brain function, especially brain development, detailed investigation of the neonicotinoids is needed to protect the health of human children. We aimed to determine the effects of neonicotinoids on the nAChRs of developing mammalian neurons and compare their effects with nicotine, a neurotoxin of brain development. METHODOLOGY/PRINCIPAL FINDINGS: Primary cultures of cerebellar neurons from neonatal rats allow for examinations of the developmental neurotoxicity of chemicals because the various stages of neurodevelopment-including proliferation, migration, differentiation, and morphological and functional maturation-can be observed in vitro. Using these cultures, an excitatory Ca(2+-influx assay was employed as an indicator of neural physiological activity. Significant excitatory Ca(2+ influxes were evoked by ACE, IMI, and nicotine at concentrations greater than 1 µM in small neurons in cerebellar cultures that expressed the mRNA of the α3, α4, and α7 nAChR subunits. The firing patterns, proportion of excited neurons, and peak excitatory Ca(2+ influxes induced by ACE and IMI showed differences from those induced by nicotine. However, ACE and IMI had greater effects on mammalian neurons than those previously reported in binding assay studies. Furthermore, the effects of the neonicotinoids were significantly inhibited by the nAChR antagonists mecamylamine, α-bungarotoxin, and dihydro-β-erythroidine. CONCLUSIONS/SIGNIFICANCE: This study is the first to show that ACE, IMI, and nicotine exert similar excitatory effects

  6. Comparative morphology of dendritic arbors in populations of Purkinje cells in mouse sulcus and apex.

    Science.gov (United States)

    Nedelescu, Hermina; Abdelhack, Mohamed

    2013-01-01

    Foliation divides the mammalian cerebellum into structurally distinct subdivisions, including the concave sulcus and the convex apex. Purkinje cell (PC) dendritic morphology varies between subdivisions and changes significantly ontogenetically. Since dendritic morphology both enables and limits sensory-motor circuit function, it is important to understand how neuronal architectures differ between brain regions. This study employed quantitative confocal microcopy to reconstruct dendritic arbors of cerebellar PCs expressing green fluorescent protein and compared arbor morphology between PCs of sulcus and apex in young and old mice. Arbors were digitized from high z-resolution (0.25 µm) image stacks using an adaptation of Neurolucida's (MBF Bioscience) continuous contour tracing tool, designed for drawing neuronal somata. Reconstructed morphologies reveal that dendritic arbors of sulcus and apex exhibit profound differences. In sulcus, 72% of the young PC population possesses two primary dendrites, whereas in apex, only 28% do. Spatial constraints in the young sulcus cause significantly more dendritic arbor overlap than in young apex, a distinction that disappears in adulthood. However, adult sulcus PC arbors develop a greater number of branch crossings. These results suggest developmental neuronal plasticity that enables cerebellar PCs to attain correct functional adult architecture under different spatial constraints.

  7. Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites.

    Directory of Open Access Journals (Sweden)

    Fabrice Ango

    2008-04-01

    Full Text Available The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1 is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.

  8. HERC 1 ubiquitin ligase mutation affects neocortical, CA3 hippocampal and spinal cord projection neurons. An ultrastructural study

    Directory of Open Access Journals (Sweden)

    Rocío eRuiz

    2016-04-01

    Full Text Available The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and, hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

  9. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

    Science.gov (United States)

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity. PMID:27147983

  10. Cerebellar distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat

    DEFF Research Database (Denmark)

    Edvinsson, Lars; Eftekhari, Sajedeh; Salvatore, Christopher A;

    2011-01-01

    Clinical and experimental results have revealed a fundamental role of calcitonin gene-related peptide (CGRP) in primary headaches. CGRP is widely expressed in neurons both in the central nervous system (CNS) and in peripheral sensory nerves. In the CNS there is a wide distribution of CGRP...... modifying protein type 1 (RAMP1) have been developed. In the present study we therefore examined immunohistochemically the distribution of CGRP and its receptor components in the cerebellum. CGRP immunoreactivity was only found intracellularly in the cerebellar Purkinje cell bodies, whereas CLR and RAMP1...... were detected on the surface of the Purkinje cell bodies and in their processes. The elaborate dendritic tree of Purkinje cell fibers was distinctly visualized with the RAMP1 antibody. In addition, profoundly stained fibers spanning from the molecular layer into the medulla was observed with the RAMP1...

  11. Valine but not leucine or isoleucine supports neurotransmitter glutamate synthesis during synaptic activity in cultured cerebellar neurons.

    Science.gov (United States)

    Bak, Lasse K; Johansen, Maja L; Schousboe, Arne; Waagepetersen, Helle S

    2012-09-01

    Synthesis of neuronal glutamate from α-ketoglutarate for neurotransmission necessitates an amino group nitrogen donor; however, it is not clear which amino acid(s) serves this role. Thus, the ability of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, to act as amino group nitrogen donors for synthesis of vesicular neurotransmitter glutamate was investigated in cultured mouse cerebellar (primarily glutamatergic) neurons. The cultures were superfused in the presence of (15) N-labeled BCAAs, and synaptic activity was induced by pulses of N-methyl-D-aspartate (300 μM), which results in release of vesicular glutamate. At the end of the superfusion experiment, the vesicular pool of glutamate was released by treatment with α-latrotoxin (3 nM, 5 min). This experimental paradigm allows a separate analysis of the cytoplasmic and vesicular pools of glutamate. Amount and extent of (15) N labeling of intracellular amino acids plus vesicular glutamate were analyzed employing HPLC and LC-MS analysis. Only when [(15) N]valine served as precursor did the labeling of both cytoplasmic and vesicular glutamate increase after synaptic activity. In addition, only [(15) N]valine was able to maintain the amount of vesicular glutamate during synaptic activity. This indicates that, among the BCAAs, only valine supports the increased need for synthesis of vesicular glutamate.

  12. Long-Term Spatiotemporal Reconfiguration of Neuronal Activity Revealed by Voltage-Sensitive Dye Imaging in the Cerebellar Granular Layer.

    Science.gov (United States)

    Gandolfi, Daniela; Mapelli, Jonathan; D'Angelo, Egidio

    2015-01-01

    Understanding the spatiotemporal organization of long-term synaptic plasticity in neuronal networks demands techniques capable of monitoring changes in synaptic responsiveness over extended multineuronal structures. Among these techniques, voltage-sensitive dye imaging (VSD imaging) is of particular interest due to its good spatial resolution. However, improvements of the technique are needed in order to overcome limits imposed by its low signal-to-noise ratio. Here, we show that VSD imaging can detect long-term potentiation (LTP) and long-term depression (LTD) in acute cerebellar slices. Combined VSD imaging and patch-clamp recordings revealed that the most excited regions were predominantly associated with granule cells (GrCs) generating EPSP-spike complexes, while poorly responding regions were associated with GrCs generating EPSPs only. The correspondence with cellular changes occurring during LTP and LTD was highlighted by a vector representation obtained by combining amplitude with time-to-peak of VSD signals. This showed that LTP occurred in the most excited regions lying in the core of activated areas and increased the number of EPSP-spike complexes, while LTD occurred in the less excited regions lying in the surround. VSD imaging appears to be an efficient tool for investigating how synaptic plasticity contributes to the reorganization of multineuronal activity in neuronal circuits. PMID:26294979

  13. Long-Term Spatiotemporal Reconfiguration of Neuronal Activity Revealed by Voltage-Sensitive Dye Imaging in the Cerebellar Granular Layer

    Directory of Open Access Journals (Sweden)

    Daniela Gandolfi

    2015-01-01

    Full Text Available Understanding the spatiotemporal organization of long-term synaptic plasticity in neuronal networks demands techniques capable of monitoring changes in synaptic responsiveness over extended multineuronal structures. Among these techniques, voltage-sensitive dye imaging (VSD imaging is of particular interest due to its good spatial resolution. However, improvements of the technique are needed in order to overcome limits imposed by its low signal-to-noise ratio. Here, we show that VSD imaging can detect long-term potentiation (LTP and long-term depression (LTD in acute cerebellar slices. Combined VSD imaging and patch-clamp recordings revealed that the most excited regions were predominantly associated with granule cells (GrCs generating EPSP-spike complexes, while poorly responding regions were associated with GrCs generating EPSPs only. The correspondence with cellular changes occurring during LTP and LTD was highlighted by a vector representation obtained by combining amplitude with time-to-peak of VSD signals. This showed that LTP occurred in the most excited regions lying in the core of activated areas and increased the number of EPSP-spike complexes, while LTD occurred in the less excited regions lying in the surround. VSD imaging appears to be an efficient tool for investigating how synaptic plasticity contributes to the reorganization of multineuronal activity in neuronal circuits.

  14. Neuronal classification and marker gene identification via single-cell expression profiling of brainstem vestibular neurons subserving cerebellar learning

    OpenAIRE

    Kodama, Takashi; Guerrero, Shiloh; Shin, Minyoung; Moghadam, Seti; Faulstich, Michael; du Lac, Sascha

    2012-01-01

    Identification of marker genes expressed in specific cell types is essential for the genetic dissection of neural circuits. Here we report a new strategy for classifying heterogeneous populations of neurons into functionally distinct types and for identifying associated marker genes. Quantitative single-cell expression profiling of genes related to neurotransmitters and ion channels enables functional classification of neurons; transcript profiles for marker gene candidates identify molecular...

  15. Encoding of action by the Purkinje cells of the cerebellum.

    Science.gov (United States)

    Herzfeld, David J; Kojima, Yoshiko; Soetedjo, Robijanto; Shadmehr, Reza

    2015-10-15

    Execution of accurate eye movements depends critically on the cerebellum, suggesting that the major output neurons of the cerebellum, Purkinje cells, may predict motion of the eye. However, this encoding of action for rapid eye movements (saccades) has remained unclear: Purkinje cells show little consistent modulation with respect to saccade amplitude or direction, and critically, their discharge lasts longer than the duration of a saccade. Here we analysed Purkinje-cell discharge in the oculomotor vermis of behaving rhesus monkeys (Macaca mulatta) and found neurons that increased or decreased their activity during saccades. We estimated the combined effect of these two populations via their projections to the caudal fastigial nucleus, and uncovered a simple-spike population response that precisely predicted the real-time motion of the eye. When we organized the Purkinje cells according to each cell's complex-spike directional tuning, the simple-spike population response predicted both the real-time speed and direction of saccade multiplicatively via a gain field. This suggests that the cerebellum predicts the real-time motion of the eye during saccades via the combined inputs of Purkinje cells onto individual nucleus neurons. A gain-field encoding of simple spikes emerges if the Purkinje cells that project onto a nucleus neuron are not selected at random but share a common complex-spike property. PMID:26469054

  16. Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice.

    Science.gov (United States)

    Mendonça, Liliana S; Nóbrega, Clévio; Hirai, Hirokazu; Kaspar, Brian K; Pereira de Almeida, Luís

    2015-02-01

    Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado-Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado-Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy.

  17. Neuritin Activates Insulin Receptor Pathway to Up-regulate Kv4.2-mediated Transient Outward K+ Current in Rat Cerebellar Granule Neurons*

    OpenAIRE

    Yao, Jin-jing; Gao, Xiao-Fei; Chow, Chi-Wing; Zhan, Xiao-Qin; Hu, Chang-Long; Mei, Yan-ai

    2012-01-01

    Neuritin is a new neurotrophic factor discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin also plays multiple roles in the process of neural development and synaptic plasticity. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Here, we report that neuritin specifically increases the densities of transient outward K+ currents (I A) in rat cerebellar granule neurons (CGNs) in a time- and concent...

  18. SELECTIVE EFFECTS OF DATURA STRAMONIUM ON THE GRANULAR PARALLEL FIBRES AND PURKINJE CELLS OF THE CEREBELLUM IN WISTAR RATS

    Directory of Open Access Journals (Sweden)

    Peter E. Ekanem

    2015-12-01

    Full Text Available Introduction: Datura stramonium (DS is a tropical ubiquitous shrub which is often used to increase intoxication in some beverages and is also freely used as a hallucinogen. It is a depressant of the central nervous system, yet commonly smoked in like manner tobacco. The present study investigated changes induced by intoxication with DS on the purkinje cells and parallel fibres of the cerebellum in Wistar rats to further elucidate the effects of this drug on cerebellar structure. Materials and Methods: The study was conducted on both male and female Wistar rats (200-250 g. They were placed into three batches and four groups were derived from each batch, with eight animals per group. Ethanolic dried seed extract of DS was diluted in normal saline and administered intraperitoneally (I.P. at a dose of 750mg/kg and given to the treatment groups: once in batch 1, twice in batch 2, twelve hourly and thrice in batch 3, eight hourly per day respectively for 4 weeks, while the control groups received an equivalent of normal saline. The rats were euthanized and sections of the cerebellum were histologically processed in all groups. Silver impregnation stain for degenerating axons and neurons was used to elucidate the actions of DS on purkinje cells and the parallel fibres of the cerebellum. Results: The result of IP administration of DS extract (750 mg/kg given three times daily to the treated rats showed significant histological changes, which included atrophy of the parallel fibres but no significant changes in the purkinje cells of the cerebellum. Conclusions: Intoxication of DS seed as a result of excessive ingestion may have a selective degenerative effect on the parallel fibres of the granule cells of the cerebellum while the purkinje cells are spared; the implication being motor dysfunction.

  19. Efficient differentiation of human embryonic stem cells into functional cerebellar-like cells.

    Science.gov (United States)

    Erceg, Slaven; Ronaghi, Mohammad; Zipancic, Ivan; Lainez, Sergio; Roselló, Mireia Gárcia; Xiong, Chen; Moreno-Manzano, Victoria; Rodríguez-Jiménez, Fernando Javier; Planells, Rosa; Alvarez-Dolado, Manuel; Bhattacharya, Shom Shanker; Stojkovic, Miodrag

    2010-11-01

    The cerebellum has critical roles in motor and sensory learning and motor coordination. Many cerebellum-related disorders indicate cell therapy as a possible treatment of neural loss. Here we show that application of inductive signals involved in early patterning of the cerebellar region followed by application of different factors directs human embryonic stem cell differentiation into cerebellar-like cells such as granule neurons, Purkinje cells, interneuron, and glial cells. Neurons derived using our protocol showed a T-shaped polarity phenotype and express similar markers to the developed human cerebellum. Electrophysiological measurements confirmed functional electrical properties compatible with these cells. In vivo implantation of differentiated human embryonic stem cells transfected with MATH1-GFP construct into neonatal mice resulted in cell migration across the molecular and the Purkinje cell layers and settlement in the internal molecular layers. Our findings demonstrate that the universal mechanisms involved in the development of cerebellum can be efficiently recapitulated in vitro, which enables the design of new strategies for cell replacement therapy, to study early human development and pathogenesis of neurodegenerative diseases. PMID:20521974

  20. A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice.

    Science.gov (United States)

    Clopath, Claudia; Badura, Aleksandra; De Zeeuw, Chris I; Brunel, Nicolas

    2014-05-21

    Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions.

  1. Cr (VI) induced oxidative stress and toxicity in cultured cerebellar granule neurons at different stages of development and protective effect of Rosmarinic acid.

    Science.gov (United States)

    Dashti, Abolfazl; Soodi, Maliheh; Amani, Nahid

    2016-03-01

    Chromium (Cr) is a widespread metal ion in the workplace, industrial effluent, and water. The toxicity of chromium (VI) on various organs including the liver, kidneys, and lung were studied, but little is known about neurotoxicity. In this study, neurotoxic effects of Cr (VI) have been investigated by cultured cerebellar granule neurons (CGNs). Immature and mature neurons were exposed to different concentrations of potassium dichromate for 24 h and cytotoxicity was measured by MTT assay. In addition, immature neurons were exposed for 5 days as regards cytotoxic effect in development stages. The reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and the protective effect of Rosmarinic acid on mature and immature neurons exposed to potassium dichromate, were measured. Furthermore, lipid peroxidation, glutathione peroxidase (GPx), and acetylcholinesterase activity in mature neurons were assessed following exposure to potassium dichromate. The results indicate that toxicity of Cr (VI) dependent on maturation steps. Cr (VI) was less toxic for immature neurons. Also, Cr (VI) induced MMP reduction and ROS production in both immature and mature neurons. In Cr (VI) treated neurons, increased lipid peroxidation and GPx activity but not acetylcholinesterase activity was observed. Interestingly, Rosmarinic acid, as a natural antioxidant, could protect mature but not immature neurons against Cr (VI) induced toxicity. Our findings revealed vulnerability of mature neurons to Cr (VI) induced toxicity and oxidative stress. PMID:25213303

  2. Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review.

    Science.gov (United States)

    Venkatraman, Anand; Opal, Puneet

    2016-08-01

    The ataxic syndrome associated with Anti-Yo antibody, or Purkinje cell cytoplasmic antibody type 1 (PCA1), is the most common variant of paraneoplastic cerebellar degeneration (PCD). The typical presentation involves the subacute development of pancerebellar deficits with a clinical plateau within 6 months. The vast majority of cases have been reported in women with pelvic or breast tumors. Magnetic resonance imaging of the brain is often normal in the early stages, with cerebellar atrophy seen later. The underlying mechanism is believed to be an immunological reaction to cerebellar degeneration-related protein 2 (CDR2), a protein usually found in the cerebellum that is ectopically produced by tumor cells. Although both B- and T-cell abnormalities are seen, there is debate about the relative importance of the autoantibodies and cytotoxic T lymphocytes in the neuronal loss. Cerebrospinal fluid abnormalities, primarily elevated protein, lymphocytic pleocytosis, and oligoclonal bands, are common in the early stages. The low prevalence of this condition has not allowed for large-scale randomized controlled trials. Immunotherapies, such as steroids, intravenous immune globulins, and plasma exchange, have been extensively used in managing this condition, with limited success. Although some reports indicate benefit from antitumor therapies like surgery and chemotherapy, this has not been consistently observed. The prognosis for anti-Yo PCD is almost uniformly poor, with most patients left bedridden. Further studies are required to clarify the pathophysiology and provide evidence-based treatment options. PMID:27606347

  3. Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review.

    Science.gov (United States)

    Venkatraman, Anand; Opal, Puneet

    2016-08-01

    The ataxic syndrome associated with Anti-Yo antibody, or Purkinje cell cytoplasmic antibody type 1 (PCA1), is the most common variant of paraneoplastic cerebellar degeneration (PCD). The typical presentation involves the subacute development of pancerebellar deficits with a clinical plateau within 6 months. The vast majority of cases have been reported in women with pelvic or breast tumors. Magnetic resonance imaging of the brain is often normal in the early stages, with cerebellar atrophy seen later. The underlying mechanism is believed to be an immunological reaction to cerebellar degeneration-related protein 2 (CDR2), a protein usually found in the cerebellum that is ectopically produced by tumor cells. Although both B- and T-cell abnormalities are seen, there is debate about the relative importance of the autoantibodies and cytotoxic T lymphocytes in the neuronal loss. Cerebrospinal fluid abnormalities, primarily elevated protein, lymphocytic pleocytosis, and oligoclonal bands, are common in the early stages. The low prevalence of this condition has not allowed for large-scale randomized controlled trials. Immunotherapies, such as steroids, intravenous immune globulins, and plasma exchange, have been extensively used in managing this condition, with limited success. Although some reports indicate benefit from antitumor therapies like surgery and chemotherapy, this has not been consistently observed. The prognosis for anti-Yo PCD is almost uniformly poor, with most patients left bedridden. Further studies are required to clarify the pathophysiology and provide evidence-based treatment options.

  4. Adaptive robotic control driven by a versatile spiking cerebellar network.

    Science.gov (United States)

    Casellato, Claudia; Antonietti, Alberto; Garrido, Jesus A; Carrillo, Richard R; Luque, Niceto R; Ros, Eduardo; Pedrocchi, Alessandra; D'Angelo, Egidio

    2014-01-01

    The cerebellum is involved in a large number of different neural processes, especially in associative learning and in fine motor control. To develop a comprehensive theory of sensorimotor learning and control, it is crucial to determine the neural basis of coding and plasticity embedded into the cerebellar neural circuit and how they are translated into behavioral outcomes in learning paradigms. Learning has to be inferred from the interaction of an embodied system with its real environment, and the same cerebellar principles derived from cell physiology have to be able to drive a variety of tasks of different nature, calling for complex timing and movement patterns. We have coupled a realistic cerebellar spiking neural network (SNN) with a real robot and challenged it in multiple diverse sensorimotor tasks. Encoding and decoding strategies based on neuronal firing rates were applied. Adaptive motor control protocols with acquisition and extinction phases have been designed and tested, including an associative Pavlovian task (Eye blinking classical conditioning), a vestibulo-ocular task and a perturbed arm reaching task operating in closed-loop. The SNN processed in real-time mossy fiber inputs as arbitrary contextual signals, irrespective of whether they conveyed a tone, a vestibular stimulus or the position of a limb. A bidirectional long-term plasticity rule implemented at parallel fibers-Purkinje cell synapses modulated the output activity in the deep cerebellar nuclei. In all tasks, the neurorobot learned to adjust timing and gain of the motor responses by tuning its output discharge. It succeeded in reproducing how human biological systems acquire, extinguish and express knowledge of a noisy and changing world. By varying stimuli and perturbations patterns, real-time control robustness and generalizability were validated. The implicit spiking dynamics of the cerebellar model fulfill timing, prediction and learning functions. PMID:25390365

  5. GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons

    Science.gov (United States)

    Lu, Jun-Mei; Wang, Chang-Ying; Hu, Changlong; Fang, Yan-Jia; Mei, Yan-Ai

    2016-01-01

    GDF-15 (growth/differentiation factor 15) is a novel member of the TGF (transforming growth factor)-β superfamily that has critical roles in the central and peripheral nervous systems. We reported previously that GDF-15 increased delayed rectifier outward K+ currents and Kv2.1 α subunit expression through TβRII (TGF-β receptor II) to activate Src kinase and Akt/mTOR (mammalian target of rapamycin) signalling in rat CGNs (cerebellar granule neurons). In the present study, we found that treatment of CGNs with GDF-15 for 24 h increased the intracellular Ca2+ concentration ([Ca2+]i) in response to membrane depolarization, as determined by Ca2+ imaging. Whole-cell current recordings indicated that GDF-15 increased the inward Ca2+ current (ICa) without altering steady-state activation of Ca2+ channels. Treatment with nifedipine, an inhibitor of L-type Ca2+ channels, abrogated GDF-15-induced increases in [Ca2+]i and ICa. The GDF-15-induced increase in ICa was mediated via up-regulation of the Cav1.3 α subunit, which was attenuated by inhibiting Akt/mTOR and ERK (extracellular-signal-regulated kinase) pathways and by pharmacological inhibition of Src-mediated TβRII phosphorylation. Given that Cav1.3 is not only a channel for Ca2+ influx, but also a transcriptional regulator, our data confirm that GDF-15 induces protein expression via TβRII and activation of a non-Smad pathway, and provide novel insight into the mechanism of GDF-15 function in neurons. PMID:27114559

  6. Transferences of Purkinje systems

    Directory of Open Access Journals (Sweden)

    W. F. Harris

    2011-12-01

    Full Text Available The transferences of heterocentric astigmatic Purkinje systems are special: submatrices B and C, that is, the disjugacy and the divergence of the system, are symmetric and submatrix D (the divarication is the transpose of submatrix A (the dilation.  It is the primary purpose of this paper to provide a proof.  The paper also derives other relationships among the fundamental properties and compact expressions for the transference and optical axis locator of a Purkinje system. (S Afr Optom 2011 70(2 57-60

  7. Enrichment of GABARAP relative to LC3 in the axonal initial segments of neurons.

    Directory of Open Access Journals (Sweden)

    Masato Koike

    Full Text Available GABAA receptor-associated protein (GABARAP was initially identified as a protein that interacts with GABAA receptor. Although LC3 (microtubule-associated protein 1 light chain 3, a GABARAP homolog, has been localized in the dendrites and cell bodies of neurons under normal conditions, the subcellular distribution of GABARAP in neurons remains unclear. Subcellular fractionation indicated that endogenous GABARAP was localized to the microsome-enriched and synaptic vesicle-enriched fractions of mouse brain as GABARAP-I, an unlipidated form. To investigate the distribution of GABARAP in neurons, we generated GFP-GABARAP transgenic mice. Immunohistochemistry in these transgenic mice showed that positive signals for GFP-GABARAP were widely distributed in neurons in various brain regions, including the hippocampus and cerebellum. Interestingly, intense diffuse and/or fibrillary expression of GFP-GABARAP was detected along the axonal initial segments (AIS of hippocampal pyramidal neurons and cerebellar Purkinje cells, in addition to the cell bodies and dendrites of these neurons. In contrast, only slight amounts of LC3 were detected along the AIS of these neurons, while diffuse and/or fibrillary staining for LC3 was mainly detected in their cell bodies and dendrites. These results indicated that, compared with LC3, GABARAP is enriched in the AIS, in addition to the cell bodies and dendrites, of these hippocampal pyramidal neurons and cerebellar Purkinje cells.

  8. Sonic hedgehog patterning during cerebellar development.

    Science.gov (United States)

    De Luca, Annarita; Cerrato, Valentina; Fucà, Elisa; Parmigiani, Elena; Buffo, Annalisa; Leto, Ketty

    2016-01-01

    The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions. PMID:26499980

  9. Evolving Models of Pavlovian Conditioning : Cerebellar Cortical Dynamics in Awake Behaving Mice

    NARCIS (Netherlands)

    Ten Brinke, Michiel M; Boele, Henk-Jan; Spanke, Jochen K; Potters, Jan-Willem; Kornysheva, Katja; Wulff, Peer; IJpelaar, Anna C H G; Koekkoek, Sebastiaan K E; De Zeeuw, Chris I

    2015-01-01

    Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs).

  10. A signal processing analysis of Purkinje cells in vitro

    Directory of Open Access Journals (Sweden)

    Ze'ev R Abrams

    2010-05-01

    Full Text Available Cerebellar Purkinje cells in vitro fire recurrent sequences of Sodium and Calcium spikes. Here, we analyze the Purkinje cell using harmonic analysis, and our experiments reveal that its output signal is comprised of three distinct frequency bands, which are combined using Amplitude and Frequency Modulation (AM/FM. We find that the three characteristic frequencies - Sodium, Calcium and Switching – occur in various combinations in all waveforms observed using whole-cell current clamp recordings. We found that the Calcium frequency can display a frequency doubling of its frequency mode, and the Switching frequency can act as a possible generator of pauses that are typically seen in Purkinje output recordings. Using a reversibly photo-switchable kainate receptor agonist, we demonstrate the external modulation of the Calcium and Switching frequencies. These experiments and Fourier analysis suggest that the Purkinje cell can be understood as a harmonic signal oscillator, enabling a higher level of interpretation of Purkinje signaling based on modern signal processing techniques.

  11. EMERGENCE OF A 600-HZ BUZZ UP STATE PURKINJE CELL FIRING IN ALERT MICE

    OpenAIRE

    Cheron, G.; Prigogine, C.; CHERON, J.; MÁRQUEZ-RUIZ, J.; Traub, R.D.; B. Dan

    2014-01-01

    Purkinje cell (PC) firing represents the sole output from the cerebellar cortex onto the deep cerebellar and vestibular nuclei. Here, we explored the different modes of PC firing in alert mice by extracellular recording. We confirm the existence of a tonic and/or bursting and quiescent modes corresponding to UP and DOWN state, respectively. We demonstrate the existence of a novel 600-Hz buzz UP state of firing characterized by simple spikes (SS) of very small amplitude. Climbing fiber (CF) in...

  12. Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.

    Science.gov (United States)

    Chung, Chan; Puthanveetil, Prasanth; Ory, Daniel S; Lieberman, Andrew P

    2016-04-01

    Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease. PMID:26908626

  13. Cell Signaling and Neurotoxicity: 3H-Arachidonic acid release (Phospholipase A2) in cerebellar granule neurons

    Science.gov (United States)

    Cell signaling is a complex process which controls basic cellular activities and coordinates actions to maintain normal cellular homeostasis. Alterations in signaling processes have been associated with neurological diseases such as Alzheimer's and cerebellar ataxia, as well as, ...

  14. New supervised learning theory applied to cerebellar modeling for suppression of variability of saccade end points.

    Science.gov (United States)

    Fujita, Masahiko

    2013-06-01

    A new supervised learning theory is proposed for a hierarchical neural network with a single hidden layer of threshold units, which can approximate any continuous transformation, and applied to a cerebellar function to suppress the end-point variability of saccades. In motor systems, feedback control can reduce noise effects if the noise is added in a pathway from a motor center to a peripheral effector; however, it cannot reduce noise effects if the noise is generated in the motor center itself: a new control scheme is necessary for such noise. The cerebellar cortex is well known as a supervised learning system, and a novel theory of cerebellar cortical function developed in this study can explain the capability of the cerebellum to feedforwardly reduce noise effects, such as end-point variability of saccades. This theory assumes that a Golgi-granule cell system can encode the strength of a mossy fiber input as the state of neuronal activity of parallel fibers. By combining these parallel fiber signals with appropriate connection weights to produce a Purkinje cell output, an arbitrary continuous input-output relationship can be obtained. By incorporating such flexible computation and learning ability in a process of saccadic gain adaptation, a new control scheme in which the cerebellar cortex feedforwardly suppresses the end-point variability when it detects a variation in saccadic commands can be devised. Computer simulation confirmed the efficiency of such learning and showed a reduction in the variability of saccadic end points, similar to results obtained from experimental data.

  15. Lack of connexin43-mediated Bergmann glial gap junctional coupling does not affect cerebellar long-term depression, motor coordination, or eyeblink conditioning

    Directory of Open Access Journals (Sweden)

    Mika Tanaka

    2008-04-01

    Full Text Available Bergmann glial cells are specialized astrocytes in the cerebellum. In the mature cerebellar molecular layer, Bergmann glial processes are closely associated with Purkinje cells, enclosing Purkinje cell dendritic synapses with a glial sheath. There is intensive gap junctional coupling between Bergmann glial processes, but their significance in cerebellar functions is not known. Connexin43 (Cx43, a major component of astrocytic gap junction channels, is abundantly expressed in Bergmann glial cells. To examine the role of Cx43-mediated gap junctions between Bergmann glial cells in cerebellar functions, we generated Cx43 conditional knockout mice with the S100b-Cre transgenic line (Cx43fl/fl:S100b-Cre, which exhibited a significant loss of Cx43 in the Bergmann glial cells and astrocytes in the cerebellum with a postnatal onset. The Cx43fl/fl:S100b-Cre mice had normal cerebellar architecture. Although gap junctional coupling between the Bergmann glial cells measured by spreading of microinjected Lucifer yellow was virtually abolished in Cx43fl/fl:S100b-Cre mice, electrophysiologic analysis revealed that cerebellar long-term depression could be induced and maintained normally in thier cerebellar slices. In addition, at the behavioral level, Cx43fl/fl:S100b-Cre mice had normal motor coordination in the rotarod task and normal conditioned eyelid response. Our findings suggest that Cx43-mediated gap junctional coupling between Bergmann glial cells is not necessary for the neuron-glia interactions required for cerebellum-dependent motor coordination and motor learning.

  16. Characterization of two novel nuclear BTB/POZ domain zinc finger isoforms. Association with differentiation of hippocampal neurons, cerebellar granule cells, and macroglia

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Kjaerulff, Karen M; Pedersen, Hans C;

    2002-01-01

    BTB/POZ (broad complex tramtrack bric-a-brac/poxvirus and zinc finger) zinc finger factors are a class of nuclear DNA-binding proteins involved in development, chromatin remodeling, and cancer. However, BTB/POZ domain zinc finger factors linked to development of the mammalian cerebral cortex......, cerebellum, and macroglia have not been described previously. We report here the isolation and characterization of two novel nuclear BTB/POZ domain zinc finger isoforms, designated HOF(L) and HOF(S), that are specifically expressed in early hippocampal neurons, cerebellar granule cells, and gliogenic...

  17. GABA agonist induced changes in ultrastructure and GABA receptor expression in cerebellar granule cells is linked to hyperpolarization of the neurons

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, G H; Schousboe, A

    1990-01-01

    GABA has been shown to exert a neurotrophic like activity by enhancing the morphological and functional maturation of neurons. Mechanisms involved in this effect of GABA are largely unknown but since GABA has been shown to mediate a hyperpolarizing action on neurons it can be assumed...... that this action might be important. In order to investigate this possibility, the ability to mimic the trophic actions of GABA of different agents known to influence the membrane potential or the GABA gated chloride channels was studied. Hence, GABA receptor expression as well as the ultrastructure of cerebellar...... granule cells were monitored after exposure of the cells in culture to either bromide, valinomycin or picrotoxin. It was found that cells which at early developmental stages (4 days in culture) were exposed to bromide or valinomycin expressed low affinity GABA receptors similar to cells treated...

  18. GABA agonist induced changes in ultrastructure and GABA receptor expression in cerebellar granule cells is linked to hyperpolarization of the neurons

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, Gert Helge; Schousboe, A

    1990-01-01

    GABA has been shown to exert a neurotrophic like activity by enhancing the morphological and functional maturation of neurons. Mechanisms involved in this effect of GABA are largely unknown but since GABA has been shown to mediate a hyperpolarizing action on neurons it can be assumed that this...... action might be important. In order to investigate this possibility, the ability to mimic the trophic actions of GABA of different agents known to influence the membrane potential or the GABA gated chloride channels was studied. Hence, GABA receptor expression as well as the ultrastructure of cerebellar...... granule cells were monitored after exposure of the cells in culture to either bromide, valinomycin or picrotoxin. It was found that cells which at early developmental stages (4 days in culture) were exposed to bromide or valinomycin expressed low affinity GABA receptors similar to cells treated with the...

  19. Deranged calcium signaling in Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias.

    Science.gov (United States)

    Kasumu, Adebimpe; Bezprozvanny, Ilya

    2012-09-01

    Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.

  20. Potentiation of Methylmercury-Induced Death in Rat Cerebellar Granular Neurons Occurs by Further Decrease of Total Intracellular GSH with BDNF via TrkB in Vitro.

    Science.gov (United States)

    Sakaue, Motoharu; Maki, Takehiro; Kaneko, Takuya; Hemmi, Natsuko; Sekiguchi, Hitomi; Horio, Tomoyo; Kadowaki, Erina; Ozawa, Aisa; Yamamoto, Masako

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a principal factor for neurogenesis, neurodevelopment and neural survival through a BDNF receptor, tropomyosin-related kinase (Trk) B, while BDNF can also cause a decrease in the intracellular glutathione (GSH) level. We investigated the exacerbation of methylmercury-induced death of rat cerebellar granular neurons (CGNs) by BDNF in vitro. Since methylmercury can decrease intracellular GSH levels, we hypothesized that a further decrease of the intracellular GSH level is involved in the process of the exacerbation of neuronal cell death. In the present study, we established that in CGN culture, a decrease of the intracellular GSH level was further potentiated with BDNF in the process of the methylmercury-induced neuronal death and also in GSH reducer-induced neuronal death. BDNF treatment promoted the decrease in GSH levels induced by methylmercury and also by L-buthionine sulfoximine (BSO) and diethyl maleate (DEM). The promoting effect of BDNF was observed in a TrkB-vector transformant of the rat neuroblastoma B35 cell line but not in the mock-vector transformant. These results indicate that the exacerbating effect of BDNF on methylmercury-induced neuronal death in cultures of CGNs includes a further decrease of intracellular GSH levels, for which TrkB is essential. PMID:27251509

  1. Cerebellum and motor learning, motor memory and motor integration: morphology and distribution of neuropeptide Y neurons in rat cerebellar cortex%大鼠小脑皮质内神经肽Y能神经元的形态与分布小脑的运动学习、记忆及整合功能

    Institute of Scientific and Technical Information of China (English)

    王省; 孙银平; 蔡新华

    2005-01-01

    BACKGROUND: Neuropeptide Y (NPY) neurons are extensively located in various brain regions such as cerebral cortex, caudate-putamen nucleus, syslimbic system, thalamus and brain stem. They are also involved in various brain activities such as motor learning, motor memory and motor integration. Considering the fact that cerebellum can reorganize through motor learning, we tried to identify the morphology and distribution of NPY neurons in rat's cerebellar cortex to obtain the morphologic knowledge that is related to its cerebellar-cortex-based motor learning.OBJECTIVE: To investigate the morphology and distribution of NPY -immunoreactive neurons in rat's cerebellar cortex, and discuss the relationship between NPY neurons and cerebellum motor learning and motor memory.DESIGN: A single-sample-study based on animal samples.SETTING: Anatomy Department, Pathophysiology Department and Morphology Center in Xinxiang Medical College.MATERIALS: From July to December 2001, the experiment was performed at the Morphology Center in Xinxiang Medical College. Ten Sprague-Dawley (SD) rats, clean grade, regardless of their gender and weighing 100-200 g,were selected.METHODS: After intraperitoneal injection anesthesia and ascending aorta infusion fixation, the cerebellum was taken out by craniosurgery. The cerebellum was immersed in the same fixative fluid for duration of 48 hours, and then was embedded in paraffin. The next step was to make continuous sagittal sections. NPY neurons were identified by SP immunohistochemical staining, using rats cerebral section as the positive control. In the negative control, the first antibody replaced by Bovine Calf Serum(BCS), and the second antibody replaced by 0.01 mol/L PBS. Sequentially the light-microscopic observation and micrography were recorded.MAIN OUTCOME MEASUREMENTS: The Morphology and distribution of NPY neurons in rat's cerebellar cortex were taken as main outcome measurements.RESULTS: NPY-immunoreactive neurons were distributed in

  2. Activation of c—Jun and suppression of phospho—p44/42 were involved in diphenylhydantoin—induced apoptosis of cultured rat cerebellar granule neurons

    Institute of Scientific and Technical Information of China (English)

    ZHAOLing-Zhi; SUXing-Wen; HUANGYi-Jun; QIUPeng-Xin; YANGGuang-Mei

    2003-01-01

    AIM:To investigate possible intracellular signal molecules involved in diphenylhydantoin (DPH)-mediated apoptosis of cerebellar granule neurons (CGN) and explore possible nolecular mechanisms of neurotoxicity of DPH.METHODS: Fluorescein diacetate (FDA) stain, hochest 33258 stain, and agar gel electrophoresis were used to test morphological and biological characters of primary CGN and cortical neurons (CN) in the presence or absence of 100μmol/L DPH; Western blot and RT-PCR were employed to further investigate apoptotic/survival signal moleculars involved in the neuronal apoptotic signal transdution. RESULTS:DPH 100μmol/L induced a typical apoptosis of CGN but had no toxicity on CN. Cerebellar granule neural apoptosis induced by 100μmol/L DPH was significantly inhibited by pre-treatment with SB203580(10μmol/L) or CEP-11004(1μmol/L) for 1h. DPH markedly upregulated the levels of phospho-c-Jun (active c-Jun), total c-Jun protein and c-jun mRNA in CGN. The levels of phospho-c-Jun dramatically elevated by DPH at 8 h were significantly inhibited by SB203580(10μmol/L) or CEP-11004 (1μmol/L). Moreover, the activities of p44/42 (ERK1/ERK2), other members of MAP kinases and generally believed to be important survival effetors in CGN, were markedly suppressed. However, the activities of both JNK and p38 were little affected in the process of apoptosis of CGN induced by 100μmol/L DPH. CONCLUSION: The selective toxicity of DPH on CGN is likely due to its ability to induce apoptosis of CGN, it is a process involved activation of c-Jun and suppression of the activity of p44/42.

  3. YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells.

    Science.gov (United States)

    Dey, A; Robitaille, M; Remke, M; Maier, C; Malhotra, A; Gregorieff, A; Wrana, J L; Taylor, M D; Angers, S; Kenney, A M

    2016-08-11

    Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas. PMID:26725322

  4. Reevaluating the Role of LTD in Cerebellar Motor Learning

    NARCIS (Netherlands)

    M. Schonewille (Martijn); Z. Gao (Zhenyu); H.J. Boele (Henk-Jan); M.F. Vinueza Veloz (Maria); W.E. Amerika; A. Šimek (Antonia); M.T.G. Jeu (Marcel); J. Steinberg (Jordan); K. Takamiya (Kogo); F.E. Hoebeek (Freek); D. Linden (David); R. Huganir (Richard); C.I. de Zeeuw (Chris)

    2011-01-01

    textabstractLong-term depression at parallel fiber-Purkinje cell synapses (PF-PC LTD) has been proposed to be required for cerebellar motor learning. To date, tests of this hypothesis have sought to interfere with receptors (mGluR1) and enzymes (PKC, PKG, or αCamKII) necessary for induction of PF-PC

  5. Cerebellar Degeneration

    Science.gov (United States)

    ... and olivopontocerebellar degeneration, progressive degenerative disorders in which cerebellar degeneration is a key feature Friedreich’s ataxia, and other spinocerebellar ataxias, which are caused by ...

  6. Cerebellar cortical degeneration in adult American Staffordshire Terriers.

    Science.gov (United States)

    Olby, Natasha; Blot, Stephane; Thibaud, Jean-Laurent; Phillips, Jeff; O'Brien, Dennis P; Burr, Jeanne; Berg, Jason; Brown, Talmage; Breen, Matthew

    2004-01-01

    Adult-onset cerebellar cortical degeneration recently has been reported in American Staffordshire Terriers. We describe the clinical and histopathologic features of this disease and examine its mode of inheritance in 63 affected dogs. The age at which neurologic deficits 1st were recognized varied from 18 months to 9 years, with the majority of dogs presented to veterinarians between 4 and 6 years of age. Time from onset of clinical signs to euthanasia varied from 6 months to 6.5 years, with the majority of affected dogs surviving from 2 to 4 years. Initial neurologic findings included stumbling, truncal sway, and ataxia exacerbated by lifting the head up and negotiating stairs. Signs progressed to obvious ataxia characterized by dysmetria, nystagmus, coarse intention tremor, variable loss of menace reaction, marked truncal sway, and falling with transient opisthotonus. With continued progression, dogs became unable to walk without falling repeatedly. Cerebellar atrophy was visible on magnetic resonance images and on gross pathology. Histopathologic findings included marked loss of Purkinje neurons with thinning of the molecular and granular layers and increased cellularity of the cerebellar nuclei. The closest common ancestor of the dogs was born in the 1950s and inheritance was most consistent with an autosomal recessive mode of transmission with a prevalence estimated at 1 in 400 dogs. This inherited disease is comparable to the group of diseases known as spinocerebellar ataxias in humans. Many spinocerebellar ataxias in humans are caused by nucleotide repeats, and this genetic aberration merits investigation as a potential cause of the disease in American Staffordshire Terriers. PMID:15058771

  7. Exclusion of the neuronal nitric oxide synthase gene and the human achaete-scute homologue 1 gene as candidate loci for spinal cerebellar ataxia 2 (SCA2)

    Energy Technology Data Exchange (ETDEWEB)

    Twells, R.; Xu, W. [Imperial College, London (United Kingdom)]|[Institute of Animal Physiology and Genetics Research, Babraham, Cambridge (United Kingdom); Ball, D. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)] [and others

    1994-09-01

    The autosomal dominant ataxias are a heterogeneous group of disorders, characterized by progressive degeneration of the cerebellum, pons and inferior olives, as well as the spinal cord. We previously mapped the spinal cerebellar ataxia 2 locus (SCA2) to chromosome 12q23-24.1 in a large Cuban founder population, flanked by the markers D12S58 and PLA2. Anticipation is a common feature of this disorder and therefore we have examined genes in this region which contain trinucleotide repeat motifs as candidate loci for SCA2. The neuronal nitric oxide synthase gene (NOS) has recently been assigned to chromosome 12q24.2-24.3 by fluorescent in situ hybridization. Neuronal NOS is responsible for the production of nitric oxide, a neurotransmitter expressed in high levels in the cerebellum as well as other regions of the nervous system. We report here the identification and analysis of an (AAT){sub n} repeat motif in an intronic region of the neuronal NOS gene, genetic mapping data and its exclusion from being involved in SCA2. We also report the exclusion of the human achaete-scute homologue 1 gene (HASH1), instrumental in neurosensory development in mouse, from being involved in SCA2 by the analysis of a proximal (CAG){sub n} repeat motif in the Cuban pedigrees, and its genetic location on chromosome 12q.

  8. INTRINSIC ELECTRICAL PROPERTIES OF MAMMALIAN NEURONS AND CNS FUNCTION: A HISTORICAL PERSPECTIVE

    Directory of Open Access Journals (Sweden)

    Rodolfo R Llinas

    2014-11-01

    Full Text Available This brief review summarizes work done in mammalian neuroscience concerning the intrinsic electrophysiological properties of four neuronal types; Cerebellar Purkinje cells, inferior olivary cells, thalamic cells, and some cortical interneurons. It is a personal perspective addressing an interesting time in neuroscience when the reflex view of brain function, as the paradigm to understand global neuroscience, began to be modified towards one in which sensory input modulates rather than dictates brain function. The perspective of the paper is not a comprehensive description of the intrinsic electrical properties of all nerve cells but rather addresses a set of cell types that provide indicative examples of mechanisms that modulate brain function.

  9. Purkinje cell long-term depression is prevented by T-588, a neuroprotective compound that reduces cytosolic calcium release from intracellular stores

    OpenAIRE

    Kimura, Tatsuo; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

    2005-01-01

    Long-term depression (LTD) of the parallel-fiber (PF) Purkinje synapse induced by four different experimental paradigms could be prevented in rat cerebellar slices by T-588, a neuroprotective compound. The paradigms consisted of pairing PF activation with climbing-fiber activation, direct depolarization, glutamic iontophoretic depolarization, or caffeine. In all cases, LTD was determined by patch-clamp recording of PF excitatory postsynaptic currents at the Purkinje cell somata. T-588 at 1 μM...

  10. Neuroprotective Effect of Total and Sequential Extract of Scrophularia striata Boiss. in Rat Cerebellar Granule Neurons Following Glutamate- Induced Neurotoxicity: An In-vitro Study

    Science.gov (United States)

    Salavati, Parvin; Ramezani, Mina; Monsef-Esfahani, Hamid R; Hajiagha, Reza; Parsa, Maliheh; Tavajohi, Shoreh; Ostad, Seyed Nasser

    2013-01-01

    Neuroprotective effect of the extract from aerial parts of Scrophularia striata Boiss (Scrophulariaceae) was investigated against glutamate-induced neurotoxicity on cultured rat pups Cerebellar Granule Neurons (CGNs). CGNs from 8 days old Sprague-Dawley rat were prepared and cultured. The experiments were performed after 8 days in culture. The plant was collected from the northeastern part (Ruin region) of Iran and air-dried at room temperature. The total extract was prepared with maceration of prepared powder in ethanol 80% for three times. Sequential extracts were obtained using dried and powdered aerial parts with increasingly polar solvents: petroleum ether, chloroform, ethyl acetate and methanol 80% solution. Cultured cells were exposed to 125 μM of glutamate for 12 h following a 24 h of incubation with test fractions at concentration of 10 mcg/mL. Morphological assay was performed using invert light microscope after fixation and staining with haematoxylin. Neuronal viability was measured using MTT assay. Statistical analysis was done using SPSS software. One way analysis of variance (ANOVA) was performed by Tukey post-hoc test. Values were considered statistically significant when p-value ≤ 0.05. Results of this study showed a significant neuroprotective activity of high polarity methanolic fraction of aerial parts of Scrophularia striata against glutamate-induced neurotoxicity in a dosedependent manner. Treatment with 10 mcg/mL of the fractions showed the best result. PMID:24250613

  11. Characterization of isolated mouse cerebellar cell populations in vitro.

    Science.gov (United States)

    Schnitzer, J; Schachner, M

    1981-12-01

    Cells from early postnatal mouse cerebellar cortex were isolated by discontinuous BSA gradient centrifugation. Three cellular fractions were obtained and called A (interface at 0-10% BSA), B ( 10-15%) and C (15-25%). These fractions were characterized after maintenance in vitro for 3 days by indirect immunofluorescence labeling with several cell type-specific probes: Tetanus toxin was used as a neuronal marker.Under the described culture conditions Thy-1.2 antibodies served as additional markers for mature neurons and NS-4 antiserum for neurons and oligodendroglial cells. Glial fibrillary acidic (GFA) protein was used as a marker for differentiated astroglia, and fibronectin as a marker for fibroblasts. Monoclonal antibodies to 04 antigen and antiserum to corpus callosum served to distinguish oligodendroglia. Fraction C contains most of the cellular debris and cells with large cell bodies (about 20 micrometers in diameter) which are positive for Thy-1, NS-4, and tetanus toxin. By birthdate labeling with [3H]thymidine these cells can be identified as Purkinje cells and/or Golgi type II cells. Fraction B is relatively heterogeneous. It contains predominantly GFA protien-positive astroglial cells (about 50% of all cells) which can be classified into 3 morphologically distinct cell types, flat epithelioid cells and star-shaped cells with thick or very thin cellular processes. Fraction B is enriched also in 04 antigen-positive oligodendrocytes, fibronectin-positive fibroblasts and Thy-1 negative, but NS-4 and tetanus toxin positive cells with small cell bodies and many fine processes. These small neurons, putative stellate and basket cells, have many fine processes and are morphologically different from th bipolar putative granule cells, some of which are also present in this fraction. Fraction C contains predominantly small neurons, mostly putative granule cell (more than 0% of all cells) which are positive for NS-4 and tetanus toxin, but negative for Thy-1.

  12. Primary culture and identification of cerebellar granule neurons from newborn rats%新生大鼠小脑颗粒神经元原代培养与鉴定

    Institute of Scientific and Technical Information of China (English)

    周礼华; 徐淑秀; 江城梅

    2011-01-01

    目的:建立一种较为理想的小脑颗粒神经元原代培养方法.方法:取新生5~7天SD大鼠,分离小脑皮质,胰酶消化后差速贴壁,种植在预先涂有左旋多聚赖氨酸的培养板内,第3天加入阿糖胞苷纯化神经元;采用神经元特异性烯醇化酶免疫细胞荧光技术鉴定神经元.结果:细胞存活率达(98±1.07)%;24 h内基本贴壁;第3天细胞突起增多、变长;培养6~8天,细胞突起交织成网,形成典型的神经细胞网络;神经元特异性烯醇化酶鉴定神经元细胞占90%左右.结论:实验获取神经元纯度较高,是小脑颗粒神经元体外培养的一种较理想的方法.%Objective: To establish a suitable primary culture method of rat cerebellar granule neurons. Methods: Rat cerebellar granule neurons were prepared from 5 -7 day old Sprague-Dawley rat pups, the cerebella was freed of meninges, minced, trypsinized,then the cell suspension was preplated for 30 min for remove any glial cells, dissociated cells were seeded at plates which had been pre-coated with Poly-L-Lysine, arabinosylcytosine was added to the culture medium on day 3 after seeding for inhibition of non-neuronal cell division. Neurons were identified by neuron-specific enolase immunofluorescence technic. Results:The survival rate of the cells was (98 ± 1.07)% ;the neurons were affixed to the culture plate after 24 hours,neurite growth was apparently on day 3,integrated neural network was formed on day 6 - 8. Cerebellar granule neurons was about 90% by neuron-specific enolase identifying. Conclusions:Neuron purity was higher in the experiment;it is a perfect technique for primary culture of rat cerebellar granule neurons.

  13. Cerebellar Hypoplasia

    Science.gov (United States)

    ... disorders that begin in early childhood, such as ataxia telangiectasia. In an infant or young child, symptoms of a disorder that features cerebellar hypoplasia might include floppy muscle tone, developmental or ...

  14. Acute cerebellar ataxia

    Science.gov (United States)

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... Acute cerebellar ataxia in children, especially younger than age 3, may occur several weeks after an illness caused by a virus. ...

  15. Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice.

    Science.gov (United States)

    Mercer, Audrey A; Palarz, Kristin J; Tabatadze, Nino; Woolley, Catherine S; Raman, Indira M

    2016-01-01

    Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including GABRB3, which encodes GABAA receptor β3 subunits and is among the maternal alleles deleted in Angelman syndrome. We tested how this Gabrb3 m-/p+ mutation affects CbN physiology in mice, separating responses of males and females. Wild-type mice showed sex differences in synaptic excitation, inhibition, and intrinsic properties. Relative to females, CbN cells of males had smaller synaptically evoked mGluR1/5-dependent currents, slower Purkinje-mediated IPSCs, and lower spontaneous firing rates, but rotarod performances were indistinguishable. In mutant CbN cells, IPSC kinetics were unchanged, but mutant males, unlike females, showed enlarged mGluR1/5 responses and accelerated spontaneous firing. These changes appear compensatory, since mutant males but not females performed indistinguishably from wild-type siblings on the rotarod task. Thus, sex differences in cerebellar physiology produce similar behavioral output, but provide distinct baselines for responses to mutations. PMID:27077953

  16. Oral administration of PF-01247324, a subtype-selective Nav1.8 blocker, reverses cerebellar deficits in a mouse model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Shannon D Shields

    Full Text Available Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS. We previously showed that sodium channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia and MS-like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of disease in a mouse MS model; unfortunately A-803467 is not orally bioavailable, diminishing the potential for translation to human patients. In the present study, we assessed the effect of per os (p.o. dosing of a new orally bioavailable Nav1.8-selective blocker, PF-01247324, in transgenic mice expressing Nav1.8 in Purkinje neurons, and in wildtype mice in the experimental autoimmune encephalomyelitis (EAE model. PF-01247324 was administered by oral gavage at 1000 mg/kg; control groups received an equal volume of vehicle. Behavioral assays of motor coordination, grip strength, and ataxia were performed. We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. These preclinical proof-of-concept data suggest that PF-01247324, its derivatives, or other Nav1.8-selective blockers merit further study for providing symptomatic therapy for cerebellar dysfunction in MS and related disorders.

  17. Neuritin activates insulin receptor pathway to up-regulate Kv4.2-mediated transient outward K+ current in rat cerebellar granule neurons.

    Science.gov (United States)

    Yao, Jin-Jing; Gao, Xiao-Fei; Chow, Chi-Wing; Zhan, Xiao-Qin; Hu, Chang-Long; Mei, Yan-Ai

    2012-11-30

    Neuritin is a new neurotrophic factor discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin also plays multiple roles in the process of neural development and synaptic plasticity. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Here, we report that neuritin specifically increases the densities of transient outward K(+) currents (I(A)) in rat cerebellar granule neurons (CGNs) in a time- and concentration-dependent manner. Neuritin-induced amplification of I(A) is mediated by increased mRNA and protein expression of Kv4.2, the main α-subunit of I(A). Exposure of CGNs to neuritin markedly induces phosphorylation of ERK (pERK), Akt (pAkt), and mammalian target of rapamycin (pmTOR). Neuritin-induced I(A) and increased expression of Kv4.2 are attenuated by ERK, Akt, or mTOR inhibitors. Unexpectedly, pharmacological blockade of insulin receptor, but not the insulin-like growth factor 1 receptor, abrogates the effect of neuritin on I(A) amplification and Kv4.2 induction. Indeed, neuritin activates downstream signaling effectors of the insulin receptor in CGNs and HeLa. Our data reveal, for the first time, an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling. PMID:23066017

  18. Caffeine Modulates Vesicle Release and Recovery at Cerebellar Parallel Fibre Terminals, Independently of Calcium and Cyclic AMP Signalling.

    Directory of Open Access Journals (Sweden)

    Katharine L Dobson

    Full Text Available Cerebellar parallel fibres release glutamate at both the synaptic active zone and at extrasynaptic sites-a process known as ectopic release. These sites exhibit different short-term and long-term plasticity, the basis of which is incompletely understood but depends on the efficiency of vesicle release and recycling. To investigate whether release of calcium from internal stores contributes to these differences in plasticity, we tested the effects of the ryanodine receptor agonist caffeine on both synaptic and ectopic transmission.Whole cell patch clamp recordings from Purkinje neurons and Bergmann glia were carried out in transverse cerebellar slices from juvenile (P16-20 Wistar rats.Caffeine caused complex changes in transmission at both synaptic and ectopic sites. The amplitude of postsynaptic currents in Purkinje neurons and extrasynaptic currents in Bergmann glia were increased 2-fold and 4-fold respectively, but paired pulse ratio was substantially reduced, reversing the short-term facilitation observed under control conditions. Caffeine treatment also caused synaptic sites to depress during 1 Hz stimulation, consistent with inhibition of the usual mechanisms for replenishing vesicles at the active zone. Unexpectedly, pharmacological intervention at known targets for caffeine--intracellular calcium release, and cAMP signalling--had no impact on these effects.We conclude that caffeine increases release probability and inhibits vesicle recovery at parallel fibre synapses, independently of known pharmacological targets. This complex effect would lead to potentiation of transmission at fibres firing at low frequencies, but depression of transmission at high frequency connections.

  19. EFFECT OF GENISTEIN ON RAT CEREBELLAR GRANULE NEURON APOPTOSIS INDUCED BY ACRYLAMIDE%三羟异黄酮对丙烯酰胺致大鼠小脑颗粒神经元凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    周礼华; 徐淑秀; 江城梅

    2011-01-01

    目的 探讨不同浓度三羟异黄酮(GEN)对丙烯酰胺(ACR)诱导大鼠小脑颗粒神经元(CGNs)凋亡的影响.方法 取新生5-7 d SD大鼠小脑皮质细胞培养,采用神经元特异性烯醉化酶免疫细胞荧光技术鉴定神经元,将培养8d的神经元进行随机分组,正常对照组、ACR染毒组(浓度为10 mmol/L)、GEN预处理组Ⅰ、Ⅱ,Ⅲ,Ⅳ(浓度为10、25、50、100 μmol/L的GEN预先处理细胞12h,再予ACR作用 24 h).甲基噻唑基四唑(MTT)法检测神经元活性;相差显微镜及Hoechst33342染色分别观察细胞及其核形态学变化;原位细胞凋亡检测法(TUNEL)观察神经元凋亡细胞数.结果 10 μmol/L组及25 μmol/L组GEN可拮杭ACR所致的大鼠CGNs凋亡,提高神经元活性,降低TUNEL阳性细胞数,减少ACR所致的神经元胞体皱缩、细胞核固缩等特征;而50 μmol/L组及100 μmol/L组对ACR引起的神经元凋亡没有保护作用.给论一定浓度范围的三羟异黄酮可以保护丙烯酰胺所致的大鼠CGNs凋亡.%Objective To investigate the effects of genistein (GEN) on apoptosis of rat cerebellar granule neurons induced by acrylamide (ACR) . Method Rat cerebellar granule neurons were prepared from the cerebellar cortex cells of 5-7 d -old Spragule-Dawley rat pups. The neurons were identified by neuron-specific enolase immunofluorescence technic.The 8 d cultured cells were divided randomly into control group. ACR model group. GEN pretreatment group Ⅰ ,Ⅱ ,Ⅲ,Ⅳ in which the cerebellar granule neurons were pretreated with 10. 25. 50. 100 μmol/L GEN for 12 h; and the culture medium was cleared, then changed to fresh DMEM/F-12 solution with the above mentioned GEN and 10 mmol/L ACR added for 24 h.The neuronal viability was measured by metylthiazdyltetrazolium (MTT); and their nuclei were observed by phase-contrast and Hochest33342 staining separately. Neuronal apoptosis was observed by TdT-mediated dUTP nick end labeling (TUNEL).Results GEN at the dose of 10, 25

  20. Long-Term Spatiotemporal Reconfiguration of Neuronal Activity Revealed by Voltage-Sensitive Dye Imaging in the Cerebellar Granular Layer

    OpenAIRE

    Gandolfi, Daniela; Mapelli, Jonathan; D’Angelo, Egidio

    2015-01-01

    Understanding the spatiotemporal organization of long-term synaptic plasticity in neuronal networks demands techniques capable of monitoring changes in synaptic responsiveness over extended multineuronal structures. Among these techniques, voltage-sensitive dye imaging (VSD imaging) is of particular interest due to its good spatial resolution. However, improvements of the technique are needed in order to overcome limits imposed by its low signal-to-noise ratio. Here, we show that VSD imaging ...

  1. [Cerebellar stroke].

    Science.gov (United States)

    Paradowski, Michał; Zimny, Anna; Paradowski, Bogusław

    2015-01-01

    Cerebellar stroke belongs to a group of rare diseases of vascular origin. Cerebellum, supplied by three pairs of arteries (AICA, PICA, SCA) with many anastomoses between them is less susceptible for a stroke, especially ischemic one. Diagnosis of the stroke in this region is harder due to lower sensibility of commonly used CT of the head in case of stroke suspicion. The authors highlight clinical symptoms distinguishing between vascular territories or topographical locations of the stroke, diagnostic procedures, classical and surgical treatment, the most common misdiagnoses are also mentioned. The authors suggest a diagnostic and therapeutic algorithm development, including rtPA treatment criteria for ischemic cerebellar stroke. PMID:26181157

  2. Cellular and molecular basis of cerebellar development

    Science.gov (United States)

    Martinez, Salvador; Andreu, Abraham; Mecklenburg, Nora; Echevarria, Diego

    2013-01-01

    Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function. PMID:23805080

  3. Cellular and Molecular Basis of Cerebellar Development

    Directory of Open Access Journals (Sweden)

    Salvador eMartinez

    2013-06-01

    Full Text Available Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.

  4. Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo.

    Science.gov (United States)

    Kim, Ji-Yoen; Ash, Ryan T; Ceballos-Diaz, Carolina; Levites, Yona; Golde, Todd E; Smirnakis, Stelios M; Jankowsky, Joanna L

    2013-04-01

    The neonatal intraventricular injection of adeno-associated virus has been shown to transduce neurons widely throughout the brain, but its full potential for experimental neuroscience has not been adequately explored. We report a detailed analysis of the method's versatility with an emphasis on experimental applications where tools for genetic manipulation are currently lacking. Viral injection into the neonatal mouse brain is fast, easy, and accesses regions of the brain including the cerebellum and brainstem that have been difficult to target with other techniques such as electroporation. We show that viral transduction produces an inherently mosaic expression pattern that can be exploited by varying the titer to transduce isolated neurons or densely-packed populations. We demonstrate that the expression of virally-encoded proteins is active much sooner than previously believed, allowing genetic perturbation during critical periods of neuronal plasticity, but is also long-lasting and stable, allowing chronic studies of aging. We harness these features to visualise and manipulate neurons in the hindbrain that have been recalcitrant to approaches commonly applied in the cortex. We show that viral labeling aids the analysis of postnatal dendritic maturation in cerebellar Purkinje neurons by allowing individual cells to be readily distinguished, and then demonstrate that the same sparse labeling allows live in vivo imaging of mature Purkinje neurons at a resolution sufficient for complete analytical reconstruction. Given the rising availability of viral constructs, packaging services, and genetically modified animals, these techniques should facilitate a wide range of experiments into brain development, function, and degeneration. PMID:23347239

  5. Valine but not leucine or isoleucine supports neurotransmitter glutamate synthesis during synaptic activity in cultured cerebellar neurons

    DEFF Research Database (Denmark)

    Bak, Lasse Kristoffer; Johansen, Maja L.; Schousboe, Arne;

    2012-01-01

    Synthesis of neuronal glutamate from a-ketoglutarate for neurotransmission necessitates an amino group nitrogen donor; however, it is not clear which amino acid(s) serves this role. Thus, the ability of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, to act as amino...... and extent of (15) N labeling of intracellular amino acids plus vesicular glutamate were analyzed employing HPLC and LC-MS analysis. Only when [(15) N]valine served as precursor did the labeling of both cytoplasmic and vesicular glutamate increase after synaptic activity. In addition, only [(15) N]valine...... was able to maintain the amount of vesicular glutamate during synaptic activity. This indicates that, among the BCAAs, only valine supports the increased need for synthesis of vesicular glutamate. © 2012 Wiley Periodicals, Inc....

  6. Bipotential precursors of putative fibrous astrocytes and oligodendrocytes in rat cerebellar cultures express distinct surface features and neuron-like γ-aminobutyric acid transport

    International Nuclear Information System (INIS)

    When postnatal rat cerebellar cells were cultured in a chemically defined, serum-free medium, the only type of astrocyte present was unable to accumulate γ-[3H]aminobutyric acid (GABA), did not express surface antigens recognized by two monoclonal antibodies, A2B5 and LB1, and showed minimal proliferation. In these cultures, nonneuronal A2B5+, LB1+ stellate cells exhibiting neuron-like [3H]GABA uptake formed cell colonies of increasing size and were GFAP-. After about one week of culturing, the A2B5+, LB1+, GABA-uptake positive cell groups became galactocerebroside (GalCer) positive. Immunocytolysis of the A2B5+ cells at 3 and 4 days in vitro prevented the appearance of the A2B5+, LB1+, GABA-uptake positive cell colonies, and also of the GalCer+ cell groups. If 10% (vol/vol) fetal calf serum was added to 6-day cultures, the A2B5+, LB1+, GABA-uptake positive cell groups expressed GFAP and not GalCer. If the serum was added to the cultures 2 days after lysing the A2B5+ cells, only A2B5-, LB1-, GABA-uptake negative astrocytes proliferated. It is concluded that the putative fibrous astrocytes previously described in serum-containing cultures derive from bipotential precursors that differentiate into oligodendrocytes (GalCer+) in serum-free medium or into astrocytes (GFAP+) in the presence of serum, while the epithelioid A2B5-, LB1-, GABA-uptake negative astrocytes originate from a different precursor not yet identified

  7. Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice

    NARCIS (Netherlands)

    M. tenBrinke (MichielM.); H.J. Boele (Henk-Jan); J.K. Spanke (Jochen); J.W. Potters (Jan Willem); K. Kornysheva (Katja); P. Wulff (Peer); A.C.H.G. IJpelaar (Anna C.H.G.); S.K.E. Koekkoek (Bas); C.I. DeZeeuw (Chris)

    2015-01-01

    textabstractThree decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink respo

  8. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis

    Science.gov (United States)

    Black, Joel A.; Dib-Hajj, Sulayman; Baker, David; Newcombe, Jia; Cuzner, M. Louise; Waxman, Stephen G.

    2000-10-01

    Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.

  9. mGluR1-mediated excitation of cerebellar GABAergic interneurons requires both G protein-dependent and Src-ERK1/2-dependent signaling pathways.

    Directory of Open Access Journals (Sweden)

    Hideo Kubota

    Full Text Available Stimulation of type I metabotropic glutamate receptors (mGluR1/5 in several neuronal types induces slow excitatory responses through activation of transient receptor potential canonical (TRPC channels. GABAergic cerebellar molecular layer interneurons (MLIs modulate firing patterns of Purkinje cells (PCs, which play a key role in cerebellar information processing. MLIs express mGluR1, and activation of mGluR1 induces an inward current, but its precise intracellular signaling pathways are unknown. We found that mGluR1 activation facilitated spontaneous firing of mouse cerebellar MLIs through an inward current mediated by TRPC1 channels. This mGluR1-mediated inward current depends on both G protein-dependent and -independent pathways. The nonselective protein tyrosine kinase inhibitors genistein and AG490 as well as the selective extracellular signal-regulated kinase 1/2 (ERK1/2 inhibitors PD98059 and SL327 suppressed the mGluR1-mediated current responses. Following G protein blockade, the residual mGluR1-mediated inward current was significantly reduced by the selective Src tyrosine kinase inhibitor PP2. In contrast to cerebellar PCs, GABAB receptor activation in MLIs did not alter the mGluR1-mediated inward current, suggesting that there is no cross-talk between mGluR1 and GABAB receptors in MLIs. Thus, activation of mGluR1 facilitates firing of MLIs through the TRPC1-mediated inward current, which depends on not only G protein-dependent but also Src-ERK1/2-dependent signaling pathways, and consequently depresses the excitability of cerebellar PCs.

  10. A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures

    DEFF Research Database (Denmark)

    Suñol, C; Babot, Z; Cristòfol, R;

    2010-01-01

    . The distribution of GAD, GABA and the vesicular glutamate transporter VGlut-1 was assessed using specific antibodies combined with immunofluorescence microscopy. Additionally, tiagabine, SKF 89976-A, betaine, beta-alanine, nipecotic acid and guvacine were used to inhibit the GAT1, betaine/GABA (BGT1), GAT2 and GAT...... neurons constituting the majority of the cells. GABA uptake exhibited the kinetics of high affinity transport and could be partly (20%) inhibited by betaine (IC(50) 142 microM), beta-alanine (30%) and almost fully (90%) inhibited by SKF 89976-A (IC(50) 0.8 microM) or nipecotic acid and guvacine at 1 m...... is not likely involved in this redistribution since addition of 15 microM tiagabine (GAT1 inhibitor) to the culture medium had no effect on the overall GABA content of the cells. Likewise the BGT1 transporter cannot alone account for the redistribution since inclusion of 3 mM betaine in the culture medium had...

  11. Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection▿

    OpenAIRE

    Williams, Brent L.; Yaddanapudi, Kavitha; Hornig, Mady; Lipkin, W. Ian

    2006-01-01

    Infection of newborn Lewis rats with Borna disease virus (neonatal Borna disease [NBD]) results in cerebellar damage without the cellular inflammation associated with infections in later life. Purkinje cell (PC) damage has been reported for several models of early-life viral infection, including NBD; however, the time course and distribution of PC pathology have not been investigated rigorously. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD...

  12. Contribution of cerebellar sensorimotor adaptation to hippocampal spatial memory.

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Passot

    Full Text Available Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation.

  13. Encoding of action by the Purkinje cells of the cerebellum

    OpenAIRE

    Herzfeld, David J.; Kojima, Yoshiko; Soetedjo, Robijanto; Shadmehr, Reza

    2015-01-01

    Summary Execution of accurate eye movements depends critically on the cerebellum 1,2,3 , suggesting that Purkinje cells (P-cells) may predict motion of the eye. Yet, this encoding has remained a long-standing puzzle: P-cells show little consistent modulation with respect to saccade amplitude 4,5 or direction 4 , and critically, their discharge lasts longer than duration of a saccade 6,7 . Here, we analyzed P-cell discharge in the oculomotor vermis of behaving monkeys 8,9 and found neurons tha...

  14. Cerebellar Degeneration as a Rare Paraneoplastic Syndrome in a Child With Hodgkin Lymphoma.

    Science.gov (United States)

    Avramova, Boryana E; Hristova, Tanya; Yordanova, Maya; Vlahova, Irena; Muchinova, Albena; Bojinova, Veneta; Konstantinov, Dobrin

    2016-08-01

    We report a rare case of cerebellar degeneration as a paraneoplastic syndrome in an 8-year-old boy with Hodgkin lymphoma that presented during first-line treatment. Antibodies against Purkinje cells (anti-Tr antibodies) were detected in the serum of the patient. After successful treatment of the lymphoma, the cerebellar symptoms resolved partially. Childhood presentation of paraneoplastic cerebellar degeneration is extremely rare, with only a few reports in the literature. For this reason, the description of all such cases contributes to the enrichment of the medical knowledge and will improve the diagnosis and the treatment of this complication. PMID:26599987

  15. Activation of a Temporal Memory in Purkinje Cells by the mGluR7 Receptor

    Directory of Open Access Journals (Sweden)

    Fredrik Johansson

    2015-12-01

    Full Text Available Cerebellar Purkinje cells can learn to respond to a conditioned stimulus with an adaptively timed pause in firing. This response was usually ascribed to long-term depression of parallel fiber to Purkinje cell synapses but has recently been shown to be due to a previously unknown form of learning involving an intrinsic cellular timing mechanism. Here, we investigate how these responses are elicited. They are resistant to blockade of GABAergic inhibition, suggesting that they are caused by glutamate release rather than by a changed balance between GABA and glutamate. We show that the responses are abolished by antagonists of the mGlu7 receptor but not significantly affected by other glutamate antagonists. These results support the existence of a distinct learning mechanism, different from changes in synaptic strength. They also demonstrate in vivo post-synaptic inhibition mediated by glutamate and show that the mGlu7 receptor is involved in activating intrinsic temporal memory.

  16. Neuroglobin Plays a Protective Role in Arsenite-Induced Cytotoxicity by Inhibition of Cdc42 and Rac1GTPases in Rat Cerebellar Granule Neurons

    Directory of Open Access Journals (Sweden)

    Xiaona Liu

    2015-07-01

    Full Text Available Background and Aims: We have previously shown that neuroglobin (Ngb expression can be regulated by sodium arsenite (NaAsO2 exposure in rat cerebellar granule neurons (CGNs. However, the precise molecular mechanisms of Ngb action are largely unknown. Ras homolog (Rho guanosine triphosphatases (Rho GTPases are involved in the regulation of a number of cellular processes, including cell cytotoxicity. It has been reported that Ngb can act as a guanine nucleotide dissociation inhibitior (GDI role to inactivate Rho GTPases. Therefore, we investigated Rho GTPases activation induced by NaAsO2 exposure in rat CGNs and effects of Rho GTPases activation on the cells. We also investigated the role of Ngb in this process. Methods: Primary cultures of CGNs were prepared from 7-day-old Wistar rat pups. The cytotoxic effects of NaAsO2 on CGNs were evaluated using the Cell Counting Kit-8 assay and TUNEL staining. RNA interference technology was used to silence Ngb, and the subsequent effects were evaluated by quantitative RT-PCR and Western blot. Cdc42 and Rac1 activation were measured by pull-down assay and Western blot. Results: NaAsO2 induced cytotoxicity in rat CGNs, increased GTP-bound form of Cdc42 and Rac1 GTPases in the cells. Furthermore, inhibition of Cdc42 or Rac1 activity using the inhibitor ZCL278 or NSC23766 decreased apoptosis and increased cell viability in the cells exposed to NaAsO2. Using siRNA-mediated knockdown, we show that NaAsO2-induced cytotoxicity was exacerbated, activation of Cdc42 (GTP-Cdc42 and Rac1 (GTP-Rac1 was increased in Ngb RNA silencing cells. Conclusions: cytotoxic effects of NaAsO2 on rat CGNs is induced at least partly by Cdc42 and Rac1 activation, and Ngb can inhibit Cdc42 and Rac1 activation to play protective role in rat CGNs exposed to NaAsO2.

  17. Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model.

    Science.gov (United States)

    Bruinsma, Caroline F; Schonewille, Martijn; Gao, Zhenyu; Aronica, Eleonora M A; Judson, Matthew C; Philpot, Benjamin D; Hoebeek, Freek E; van Woerden, Geeske M; De Zeeuw, Chris I; Elgersma, Ype

    2015-11-01

    Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo-ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3am-/p+ mouse model of AS. VOR phase-reversal learning was singularly impaired in these animals and correlated with reduced tonic inhibition between Golgi cells and granule cells. Purkinje cell physiology, in contrast, was normal in AS mice as shown by synaptic plasticity and spontaneous firing properties that resembled those of controls. Accordingly, neither VOR phase-reversal learning nor locomotion was impaired following selective deletion of Ube3a in Purkinje cells. However, genetic normalization of αCaMKII inhibitory phosphorylation fully rescued locomotor deficits despite failing to improve cerebellar learning in AS mice, suggesting extracerebellar circuit involvement in locomotor learning. We confirmed this hypothesis through cerebellum-specific reinstatement of Ube3a, which ameliorated cerebellar learning deficits but did not rescue locomotor deficits. This double dissociation of locomotion and cerebellar phenotypes strongly suggests that the locomotor deficits of AS mice do not arise from impaired cerebellar cortex function. Our results provide important insights into the etiology of the motor deficits associated with AS. PMID:26485287

  18. Synaptic plasticity in medial vestibular nucleus neurons: comparison with computational requirements of VOR adaptation.

    Directory of Open Access Journals (Sweden)

    John R W Menzies

    Full Text Available BACKGROUND: Vestibulo-ocular reflex (VOR gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD at vestibular synapses. METHODOLOGY/PRINCIPAL FINDINGS: Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular and inhibitory (floccular inputs converging on medial vestibular nucleus (MVN neurons (input-spike-timing dependent plasticity, iSTDP. To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarization, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning. CONCLUSIONS: These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR

  19. Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.

    Science.gov (United States)

    Rath, Martin F; Rovsing, Louise; Møller, Morten

    2014-09-01

    The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators residing outside the SCN have the capacity to generate peripheral circadian rhythms. We have recently shown the presence of SCN-controlled oscillators in the neocortex and cerebellum of the rat. The function of these peripheral brain clocks is unknown, and elucidating this could involve mice with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum, as revealed by immunohistochemistry. These findings give reason to further pursue the physiological significance of circadian oscillators in the mouse neocortex and cerebellum.

  20. Multiplicative gain modulation arising from inhibitory synaptic plasticity in the cerebellar nuclei

    Directory of Open Access Journals (Sweden)

    Dimitris Bampasakis

    2014-03-01

    Full Text Available Neurons use the rate of action potentials to encode sensory variables. This makes the output rate as a function of input, also known as input-output (I–O relationship, a core computational function in neuronal processing. The introduction, or increase, of a modulatory input, can transform this function in multiple ways: additive transformations result in a shift, and multiplicative transformations in a change of slope of the I–O relationship. This slope change is known as gain modulation, and it can implement important forms of neural computation such as coordinate transformations. Gain modulation can be found in a wide range of brain systems, including the cerebellum, where it can be enabled by synaptic plasticity at both excitatory and inhibitory synapses. We use a realistic, conductance based, multi-compartmental model of a cerebellar nucleus (CN neuron, to investigate the determinants of gain modulation mediated by synaptic plasticity. In particular, we are interested in the effect of short term depression (STD at the inhibitory synapse from Purkinje cells (PCs to CN neurons. Considering the inhibitory PC input as the driving input, we compare the I–O relationship of the CN neuron in the presence and absence of STD for 20 Hz of excitatory synaptic input from mossy fibers (MFs, and find that STD introduces a gain change, changing the slope of the I–O function. We then proceed to compare the transformation performed by the increase of the modulatory input from 20 to 50 Hz, in the presence and absence of STD. We find that the presence of STD in the inhibitory synapse introduces a multiplicative component in the transformation performed by the excitatory input, an effect that persists for different levels of STD, and various combinations of regularity and synchronicity in the input.

  1. Mini-review: synaptic integration in the cerebellar nuclei--perspectives from dynamic clamp and computer simulation studies.

    Science.gov (United States)

    Jaeger, Dieter

    2011-12-01

    The cerebellar nuclei (CN) process inhibition from Purkinje cells (PC) and excitation from mossy and climbing fiber collaterals. CN neurons in slices show intrinsic pacemaking activity, which is easily modulated by synaptic inputs. Our work using dynamic clamping and computer modeling shows that synchronicity between PC inputs is an important factor in determining spike rate and spike timing of CN neurons and that brief pauses in PC inputs provide a potent stimulus to trigger CN spikes. Excitatory input can equally control spike rate, but, due to a large slow, NMDA component also amplifies responses to inhibitory inputs. Intrinsic properties of CN neurons are well suited to provide prolonged responses to strong input transients and could be involved in motor pattern generation. One such specific mechanism is given by fast and slow rebound bursting. Nevertheless, we are just beginning to unravel synaptic integration in the CN, and the outcome of the work to date is best characterized by the generation of new specific questions that lend themselves to a combined experimental and computer modeling approach in future studies.

  2. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    Science.gov (United States)

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum. PMID:26482421

  3. Transplantation and Stem Cell Therapy for Cerebellar Degenerations.

    Science.gov (United States)

    Cendelin, Jan

    2016-02-01

    Stem cell-based and regenerative therapy may become a hopeful treatment for neurodegenerative diseases including hereditary cerebellar degenerations. Neurotransplantation therapy mainly aims to substitute lost cells, but potential effects might include various mechanisms including nonspecific trophic effects and stimulation of endogenous regenerative processes and neural plasticity. Nevertheless, currently, there remain serious limitations. There is a wide spectrum of human hereditary cerebellar degenerations as well as numerous cerebellar mutant mouse strains that serve as models for the development of effective therapy. By now, transplantation has been shown to ameliorate cerebellar function, e.g. in Purkinje cell degeneration mice, Lurcher mutant mice and mouse models of spinocerebellar ataxia type 1 and type 2 and Niemann-Pick disease type C. Despite the lack of direct comparative studies, it appears that there might be differences in graft development and functioning between various types of cerebellar degeneration. Investigation of the relation of graft development to specific morphological, microvascular or biochemical features of the diseased host tissue in various cerebellar degenerations may help to identify factors determining the fate of grafted cells and potential of their functional integration. PMID:26155762

  4. HSF1-deficiency affects gait coordination and cerebellar calbindin levels.

    Science.gov (United States)

    Ingenwerth, Marc; Estrada, Veronica; Stahr, Anna; Müller, Hans Werner; von Gall, Charlotte

    2016-09-01

    Heat shock proteins (HSPs) play an important role in cell homeostasis and protect against cell damage. They were previously identified as key players in different ataxia models. HSF1 is the main transcription factor for HSP activation. HSF1-deficient mice (HSF1-/-) are known to have deficiencies in motor control test. However, little is known about effects of HSF1-deficiency on locomotor, especially gait, coordination. Therefore, we compared HSF-deficient (HSF1-/-) mice and wildtype littermates using an automated gait analysis system for objective assessment of gait coordination. We found significant changes in gait parameters of HSF1-/- mice reminiscent of cerebellar ataxia. Immunohistochemical analyses of a cerebellum revealed co-localization of HSF1 and calbindin in Purkinje cells. Therefore, we tested the hypothesis of a potential interconnection between HSF1 and calbindin in Purkinje cells. Calbindin levels were analyzed qualitatively and quantitatively by immunohistochemistry and immunoblotting, respectively. While quantitative PCR revealed no differences in calbindin mRNA levels between HSF1+/+ and HSF1-/- mice, calbindin protein levels, however, were significantly decreased in a cerebellum of HSF1-/- mice. A pathway analysis supports the hypothesis of an interconnection between HSF1 and calbindin. In summary, the targeted deletion of HSF1 results in changes of locomotor function associated with changes in cerebellar calbindin protein levels. These findings suggest a role of HSF1 in regular Purkinje cell calcium homeostasis. PMID:27173427

  5. Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABA(A) receptor δ subunit in cerebellar granule neurons and delays motor development in rats.

    Science.gov (United States)

    Diaz, Marvin R; Vollmer, Cyndel C; Zamudio-Bulcock, Paula A; Vollmer, William; Blomquist, Samantha L; Morton, Russell A; Everett, Julie C; Zurek, Agnieszka A; Yu, Jieying; Orser, Beverley A; Valenzuela, C Fernando

    2014-04-01

    Exposure to ethanol (EtOH) during fetal development can lead to long-lasting alterations, including deficits in fine motor skills and motor learning. Studies suggest that these are, in part, a consequence of cerebellar damage. Cerebellar granule neurons (CGNs) are the gateway of information into the cerebellar cortex. Functionally, CGNs are heavily regulated by phasic and tonic GABAergic inhibition from Golgi cell interneurons; however, the effect of EtOH exposure on the development of GABAergic transmission in immature CGNs has not been investigated. To model EtOH exposure during the 3rd trimester-equivalent of human pregnancy, neonatal pups were exposed intermittently to high levels of vaporized EtOH from postnatal day (P) 2 to P12. This exposure gradually increased pup serum EtOH concentrations (SECs) to ∼60 mM (∼0.28 g/dl) during the 4 h of exposure. EtOH levels gradually decreased to baseline 8 h after the end of exposure. Surprisingly, basal tonic and phasic GABAergic currents in CGNs were not significantly affected by postnatal alcohol exposure (PAE). However, PAE increased δ subunit expression at P28 as detected by immunohistochemical and western blot analyses. Also, electrophysiological studies with an agonist that is highly selective for δ-containing GABA(A) receptors, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP), showed an increase in THIP-induced tonic current. Behavioral studies of PAE rats did not reveal any deficits in motor coordination, except for a delay in the acquisition of the mid-air righting reflex that was apparent at P15 to P18. These findings demonstrate that repeated intermittent exposure to high levels of EtOH during the equivalent of the last trimester of human pregnancy has significant but relatively subtle effects on motor coordination and GABAergic transmission in CGNs in rats.

  6. A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice

    NARCIS (Netherlands)

    Clopath, Claudia; Badura, Aleksandra; De Zeeuw, Chris I; Brunel, Nicolas

    2014-01-01

    Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learni

  7. A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation

    NARCIS (Netherlands)

    A. Belmeguenai; C.R.W. Hansel (Christian)

    2005-01-01

    textabstractCerebellar parallel fiber (PF)-Purkinje cell (PC) synapses can undergo postsynaptically expressed long-term depression (LTD) or long-term potentiation (LTP). PF-LTD induction requires the coactivity of the PF and CF (climbing fiber) inputs to PCs and a concomitant calci

  8. Quantitative neuroanatomy of all Purkinje cells with light sheet microscopy and high-throughput image analysis

    Directory of Open Access Journals (Sweden)

    Ludovico eSilvestri

    2015-05-01

    Full Text Available Characterizing the cytoarchitecture of mammalian central nervous system on a brain-wide scale is becoming a compelling need in neuroscience. For example, realistic modeling of brain activity requires the definition of quantitative features of large neuronal populations in the whole brain. Quantitative anatomical maps will also be crucial to classify the cytoarchtitectonic abnormalities associated with neuronal pathologies in a high reproducible and reliable manner. In this paper, we apply recent advances in optical microscopy and image analysis to characterize the spatial distribution of Purkinje cells across the whole cerebellum. Light sheet microscopy was used to image with micron-scale resolution a fixed and cleared cerebellum of an L7-GFP transgenic mouse, in which all Purkinje cells are fluorescently labeled. A fast and scalable algorithm for fully automated cell identification was applied on the image to extract the position of all the fluorescent Purkinje cells. This vectorized representation of the cell population allows a thorough characterization of the complex three-dimensional distribution of the neurons, highlighting the presence of gaps inside the lamellar organization of Purkinje cells, whose density is believed to play a significant role in autism spectrum disorders. Furthermore, clustering analysis of the localized somata permits dividing the whole cerebellum in groups of Purkinje cells with high spatial correlation, suggesting new possibilities of anatomical partition. The quantitative approach presented here can be extended to study the distribution of different types of cell in many brain regions and across the whole encephalon, providing a robust base for building realistic computational models of the brain, and for unbiased morphological tissue screening in presence of pathologies and/or drug treatments.

  9. Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.

    Science.gov (United States)

    Caporali, Paola; Bruno, Francesco; Palladino, Giampiero; Dragotto, Jessica; Petrosini, Laura; Mangia, Franco; Erickson, Robert P; Canterini, Sonia; Fiorenza, Maria Teresa

    2016-01-01

    Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1 (nmf164) for sensorimotor development from postnatal day (PN) 3 to PN21. Npc1 (nmf164) / Npc1 (nmf164) pups displayed a 2.5-day delay in the acquisition of complex motor abilities compared to wild-type (wt) littermates, in agreement with the significant disorganization of cerebellar cortex cytoarchitecture observed between PN11 and PN15. Compared to wt, Npc1 (nmf164) homozygous mice exhibited a poorer morphological differentiation of Bergmann glia (BG), as indicated by thicker radial shafts and less elaborate reticular pattern of lateral processes. Also BG functional development was defective, as indicated by the significant reduction in GLAST and Glutamine synthetase expression. A reduced VGluT2 and GAD65 expression also indicated an overall derangement of the glutamatergic/GABAergic stimulation that PCs receive by climbing/parallel fibers and basket/stellate cells, respectively. Lastly, Npc1-deficiency also affected oligodendrocyte differentiation as indicated by the strong reduction of myelin basic protein. Two sequential 2-hydroxypropyl-β-cyclodextrin administrations at PN4 and PN7 counteract these defects, partially preventing functional impairment of BG and fully restoring the normal patterns of glutamatergic/GABAergic stimulation to PCs.These findings indicate that in Npc1 (nmf164) homozygous mice the derangement of synaptic

  10. Motor dysfunction in the tottering mouse is linked to cerebellar spontaneous low frequency oscillations revealed by flavoprotein autofluorescence optical imaging

    Science.gov (United States)

    Chen, Gang; Popa, Laurentiu S.; Wang, Xinming; Gao, Wangcai; Barnes, Justin; Hendrix, Claudia M.; Hess, Ellen J.; Ebner, Timothy J.

    2009-02-01

    Flavoprotein autofluorescence optical imaging is developing into a powerful research tool to study neural activity, particularly in vivo. In this study we used this imaging technique to investigate the neuronal mechanism underlying the episodic movement disorder that is characteristic of the tottering (tg) mouse, a model of episodic ataxia type 2. Both EA2 and the tg mouse are caused by mutations in the gene encoding Cav2.1 (P/Q-type) voltage-gated Ca2+ channels. These mutations result in a reduction in P/Q Ca2+ channel function. Both EA2 patients and tg mice have a characteristic phenotype consisting of transient motor attacks triggered by stress, caffeine or ethanol. The neural events underlying these episodes of dystonia are unknown. Flavoprotein autofluorescence optical imaging revealed spontaneous, transient, low frequency oscillations in the cerebellar cortex of the tg mouse. Lasting from 30 - 120 minutes, the oscillations originate in one area then spread to surrounding regions over 30 - 60 minutes. The oscillations are reduced by removing extracellular Ca2+ and blocking Cav 1.2/1.3 (L-type) Ca2+ channels. The oscillations are not affected by blocking AMPA receptors or by electrical stimulation of the parallel fiber - Purkinje cell circuit, suggesting the oscillations are generated intrinsically in the cerebellar cortex. Conversely, L-type Ca2+ agonists generate oscillations with similar properties. In the awake tg mouse, transcranial flavoprotein imaging revealed low frequency oscillations that are accentuated during caffeine induced attacks of dystonia. The oscillations increase during the attacks of dystonia and are coupled to oscillations in face and hindlimb EMG activity. These transient oscillations and the associated cerebellar dysfunction provide a novel mechanism by which an ion channel disorder results in episodic motor dysfunction.

  11. Dynamic distribution and stem cell characteristics of Sox1-expressing cells in the cerebellar cortex

    Institute of Scientific and Technical Information of China (English)

    Joelle Alcock; Virginie Sottile

    2009-01-01

    Bergmann glia cells are a discrete radial glia population surrounding Purkinje cells in the cerebellar cortex. Al-though Bergmann glia are essential for the development and correct arborization of Purkinje cells, little is known about the regulation of this cell population after the developmental phase. In an effort to characterize this population at the molecular level, we have analyzed marker expression and established that adult Bergmann glia express Soxl, Sox2 and Sox9, a feature otherwise associated with neural stem cells (NSCs). In the present study, we have further analyzed the developmental pattern of Soxl-expressing cells in the developing cerebellum. We report that before be-coming restricted to the Purkinje cell layer, Soxl-positive cells are present throughout the immature tissue, and that these cells show characteristics of Bergmann glia progenitors. Our study shows that these progenitors express Soxl, Sox2 and Sox9, a signature maintained throughout cerebellar maturation into adulthood. When isolated in culture, the Soxl-expressing cerebellar population exhibited neurosphere-forming ability, NSC-marker characteristics, and demonstrated multipotency at the clonal level. Our results show that the Bergmann glia population expresses Soxl during cerebellar development, and that these cells can be isolated and show stem cell characteristics in vitro, sug-gesting that they could hold a broader potential than previously thought.

  12. GDNF-induced cerebellar toxicity: A brief review.

    Science.gov (United States)

    Luz, Matthias; Mohr, Erich; Fibiger, H Christian

    2016-01-01

    Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.

  13. An amplified promoter system for targeted expression of calcium indicator proteins in the cerebellar cortex

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    Bernd eKuhn

    2012-07-01

    Full Text Available Recording of identified neuronal network activity using genetically encoded calcium indicators (GECIs requires labeling that is cell type-specific and bright enough for the detection of functional signals. However, specificity and strong expression are often not achievable using the same promoter. Here we present a combinatorial approach for targeted expression and single-cell-level quantification in which a weak promoter is used to drive trans-amplification under a strong general promoter. We demonstrated this approach using recombinant adeno-associated viruses (rAAVs to deliver the sequence of the GECI D3cpv in the mouse cerebellar cortex. Direct expression under the human synapsin promoter (hSYN led to high levels of expression (50-100 µM in five interneuron types of the cerebellar cortex but not in Purkinje cells (PCs (≤10 μM, yielding sufficient contrast to allow functional signals to be recorded from somata and processes in awake animals using two-photon microscopy. When the hSYN promoter was used to drive expression of the tetracycline transactivator (tTA, a second rAAV containing the bidirectional TET promoter (Ptetbi could drive strong D3cpv expression in PCs (10-300 µM, enough to allow reliable complex spike detection in the dendritic arbor. An amplified approach should be of use in monitoring neural processing in selected cell types and boosting expression of optogenetic probes. Additionally, we overcome cell toxicity associated with rAAV injection and/or local GECI overexpression by combining the virus injection with systemic pre-injection of hyperosmotic D-mannitol, and by this double the time window for functional imaging.

  14. Systematic regional variations in Purkinje cell spiking patterns.

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    Jianqiang Xiao

    Full Text Available In contrast to the uniform anatomy of the cerebellar cortex, molecular and physiological studies indicate that significant differences exist between cortical regions, suggesting that the spiking activity of Purkinje cells (PCs in different regions could also show distinct characteristics. To investigate this possibility we obtained extracellular recordings from PCs in different zebrin bands in crus IIa and vermis lobules VIII and IX in anesthetized rats in order to compare PC firing characteristics between zebrin positive (Z+ and negative (Z- bands. In addition, we analyzed recordings from PCs in the A2 and C1 zones of several lobules in the posterior lobe, which largely contain Z+ and Z- PCs, respectively. In both datasets significant differences in simple spike (SS activity were observed between cortical regions. Specifically, Z- and C1 PCs had higher SS firing rates than Z+ and A2 PCs, respectively. The irregularity of SS firing (as assessed by measures of interspike interval distribution was greater in Z+ bands in both absolute and relative terms. The results regarding systematic variations in complex spike (CS activity were less consistent, suggesting that while real differences can exist, they may be sensitive to other factors than the cortical location of the PC. However, differences in the interactions between SSs and CSs, including the post-CS pause in SSs and post-pause modulation of SSs, were also consistently observed between bands. Similar, though less strong trends were observed in the zonal recordings. These systematic variations in spontaneous firing characteristics of PCs between zebrin bands in vivo, raises the possibility that fundamental differences in information encoding exist between cerebellar cortical regions.

  15. Silencing the Majority of Cerebellar Granule Cells Uncovers Their Essential Role in Motor Learning and Consolidation

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    Elisa Galliano

    2013-04-01

    Full Text Available Cerebellar granule cells (GCs account for more than half of all neurons in the CNS of vertebrates. Theoretical work has suggested that the abundance of GCs is advantageous for sparse coding during memory formation. Here, we minimized the output of the majority of GCs by selectively eliminating their CaV2.1 (P/Q-type Ca2+ channels, which mediate the bulk of their neurotransmitter release. This resulted in reduced GC output to Purkinje cells (PCs and stellate cells (SCs as well as in impaired long-term plasticity at GC-PC synapses. As a consequence modulation amplitude and regularity of simple spike (SS output were affected. Surprisingly, the overall motor performance was intact, whereas demanding motor learning and memory consolidation tasks were compromised. Our findings indicate that a minority of functionally intact GCs is sufficient for the maintenance of basic motor performance, whereas acquisition and stabilization of sophisticated memories require higher numbers of normal GCs controlling PC firing.

  16. Non-linear leak currents affect mammalian neuron physiology

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    Shiwei eHuang

    2015-11-01

    Full Text Available In their seminal works on squid giant axons, Hodgkin and Huxley approximated the membrane leak current as Ohmic, i.e. linear, since in their preparation, sub-threshold current rectification due to the influence of ionic concentration is negligible. Most studies on mammalian neurons have made the same, largely untested, assumption. Here we show that the membrane time constant and input resistance of mammalian neurons (when other major voltage-sensitive and ligand-gated ionic currents are discounted varies non-linearly with membrane voltage, following the prediction of a Goldman-Hodgkin-Katz-based passive membrane model. The model predicts that under such conditions, the time constant/input resistance-voltage relationship will linearize if the concentration differences across the cell membrane are reduced. These properties were observed in patch-clamp recordings of cerebellar Purkinje neurons (in the presence of pharmacological blockers of other background ionic currents and were more prominent in the sub-threshold region of the membrane potential. Model simulations showed that the non-linear leak affects voltage-clamp recordings and reduces temporal summation of excitatory synaptic input. Together, our results demonstrate the importance of trans-membrane ionic concentration in defining the functional properties of the passive membrane in mammalian neurons as well as other excitable cells.

  17. Proteomic studies of a single CNS synapse type: the parallel fiber/purkinje cell synapse.

    Directory of Open Access Journals (Sweden)

    Fekrije Selimi

    2009-04-01

    Full Text Available Precise neuronal networks underlie normal brain function and require distinct classes of synaptic connections. Although it has been shown that certain individual proteins can localize to different classes of synapses, the biochemical composition of specific synapse types is not known. Here, we have used a combination of genetically engineered mice, affinity purification, and mass spectrometry to profile proteins at parallel fiber/Purkinje cell synapses. We identify approximately 60 candidate postsynaptic proteins that can be classified into 11 functional categories. Proteins involved in phospholipid metabolism and signaling, such as the protein kinase MRCKgamma, are major unrecognized components of this synapse type. We demonstrate that MRCKgamma can modulate maturation of dendritic spines in cultured cortical neurons, and that it is localized specifically to parallel fiber/Purkinje cell synapses in vivo. Our data identify a novel synapse-specific signaling pathway, and provide an approach for detailed investigations of the biochemical complexity of central nervous system synapse types.

  18. The critical role of lipid rafts nanodomains in the cross-talk between calcium and reactive oxygen and nitrogen species in cerebellar granule neurons apoptosis by extracellular potassium deprivation

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    Carlos Gutierrez-Merino

    2016-01-01

    Full Text Available The apoptosis of cerebellar granule neurons (CGN induced by low-potassium in serum free medium in vitro has become a widely used model for neuronal apoptosis during in vivo brain development. In this review we shall summarize first the basic features of this model for neuronal apoptosis. Next, we shall focus on the L-type calcium channels (LTCC inactivation as the primary pro-apoptotic signal in low K+-induced CGN death. This apoptotic process can be split into two major and sequential cellular signaling phases: one reversible phase that offers a temporal window for therapeutic interventions to prevent neuronal death, and an irreversible later phase. Therefore, we shall comment next the critical role of reactive oxygen species (ROS production and major ROS sources triggering the entry of CGN in the irreversible stages of low K+-induced apoptosis. Then, we shall present the experimental evidences showing clustering of LTCC and ROS producing enzymes in plasma membrane lipid rafts of CGN matured in vitro, which have opened new perspectives for cell signaling in the early and reversible phase of this apoptosis. The role of lipid rafts nanodomains as fast response calcium/nitric oxide transducers of the switch of CGN to low K+ medium will be discussed next. The two major conclusions drawn from this review are: (1 deregulation of the pool of cytochrome b5 reductase associated to plasma membrane-lipid rafts, at least in part due to overexpression of cytochrome b5, can account for the critical superoxide anion overshot which triggers the entry in the irreversible phase of low K+ apoptosis of CGN, and (2 LTCC inactivation is rapidly transduced by lipid rafts nanodomains into a large drop of cytosolic calcium, a switch-off of nitric oxide production and subsequent inactivation of survival signaling pathways dependent on the activity of CaMKII, PKA and Akt/PKB kinases.

  19. Activity of the lactate-alanine shuttle is independent of glutamate-glutamine cycle activity in cerebellar neuronal-astrocytic cultures

    DEFF Research Database (Denmark)

    Bak, Lasse K; Sickmann, Helle M; Schousboe, Arne;

    2004-01-01

    The glutamate-glutamine cycle describes the neuronal release of glutamate into the synaptic cleft, astrocytic uptake, and conversion into glutamine, followed by release for use as a neuronal glutamate precursor. This only explains the fate of the carbon atoms, however, and not that of the ammonia...

  20. Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice

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    Michiel M. ten Brinke

    2015-12-01

    Full Text Available Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs. However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS-related complex spike responses, and molecular layer interneuron (MLI activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval.

  1. At the Edge of Chaos: How Cerebellar Granular Layer Network Dynamics Can Provide the Basis for Temporal Filters.

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    Christian Rössert

    2015-10-01

    Full Text Available Models of the cerebellar microcircuit often assume that input signals from the mossy-fibers are expanded and recoded to provide a foundation from which the Purkinje cells can synthesize output filters to implement specific input-signal transformations. Details of this process are however unclear. While previous work has shown that recurrent granule cell inhibition could in principle generate a wide variety of random outputs suitable for coding signal onsets, the more general application for temporally varying signals has yet to be demonstrated. Here we show for the first time that using a mechanism very similar to reservoir computing enables random neuronal networks in the granule cell layer to provide the necessary signal separation and extension from which Purkinje cells could construct basis filters of various time-constants. The main requirement for this is that the network operates in a state of criticality close to the edge of random chaotic behavior. We further show that the lack of recurrent excitation in the granular layer as commonly required in traditional reservoir networks can be circumvented by considering other inherent granular layer features such as inverted input signals or mGluR2 inhibition of Golgi cells. Other properties that facilitate filter construction are direct mossy fiber excitation of Golgi cells, variability of synaptic weights or input signals and output-feedback via the nucleocortical pathway. Our findings are well supported by previous experimental and theoretical work and will help to bridge the gap between system-level models and detailed models of the granular layer network.

  2. Image-Based Structural Modeling of the Cardiac Purkinje Network

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    Benjamin R. Liu

    2015-01-01

    Full Text Available The Purkinje network is a specialized conduction system within the heart that ensures the proper activation of the ventricles to produce effective contraction. Its role during ventricular arrhythmias is less clear, but some experimental studies have suggested that the Purkinje network may significantly affect the genesis and maintenance of ventricular arrhythmias. Despite its importance, few structural models of the Purkinje network have been developed, primarily because current physical limitations prevent examination of the intact Purkinje network. In previous modeling efforts Purkinje-like structures have been developed through either automated or hand-drawn procedures, but these networks have been created according to general principles rather than based on real networks. To allow for greater realism in Purkinje structural models, we present a method for creating three-dimensional Purkinje networks based directly on imaging data. Our approach uses Purkinje network structures extracted from photographs of dissected ventricles and projects these flat networks onto realistic endocardial surfaces. Using this method, we create models for the combined ventricle-Purkinje system that can fully activate the ventricles through a stimulus delivered to the Purkinje network and can produce simulated activation sequences that match experimental observations. The combined models have the potential to help elucidate Purkinje network contributions during ventricular arrhythmias.

  3. Propofol effects on cerebellar long-term depression.

    Science.gov (United States)

    Lee, Kwan Young; Kim, Young Im; Kim, Se Hoon; Park, Hyung Seo; Park, Youn Joon; Ha, Myung Sook; Jin, Yunju; Kim, Dong Kwan

    2015-11-16

    Propofol is an intravenously administered anesthetic that induces γ-aminobutyric acid-mediated inhibition in the central nervous system. It has been implicated in prolonged movement disorders. Since the cerebellum is important for motor coordination and learning, we investigated the potential effects of propofol on cerebellar circuitry. Using the whole-cell patch-clamp technique in Wister rat cerebellar slices, we demonstrated that propofol administration impaired long-term depression from the parallel fiber (PF) to Purkinje cell (PC) synapses (PF-LTD). Also, propofol reduced metabotropic glutamate receptor 1 (mGluR1)-mediated and group I mGluR agonist-induced slow currents in PCs. These results suggest that the propofol-induced PF-LTD impairment may be related to an alteration in mGluR1 signaling, which is essential to motor learning. PMID:26455962

  4. Coordinated regulation of endocannabinoid-mediated retrograde synaptic suppression in the cerebellum by neuronal and astrocytic monoacylglycerol lipase

    Science.gov (United States)

    Liu, Xiaojie; Chen, Yao; Vickstrom, Casey R.; Li, Yan; Viader, Andreu; Cravatt, Benjamin F.; Liu, Qing-song

    2016-01-01

    The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic depression including depolarization-induced suppression of excitation (DSE) and inhibition (DSI). 2-AG is degraded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes. Using knockout mice in which MAGL is deleted globally or selectively in neurons or astrocytes, we investigated the relative contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells (PCs) in cerebellar slices. We report that neuronal MAGL plays a predominant role in terminating DSE at climbing fiber (CF) to PC synapses, while both neuronal and astrocytic MAGL significantly contributes to the termination of DSE at parallel fiber (PF) to PC synapses and DSI at putative Stellate cell to PC synapses. Thus, DSE and DSI at different synapses is not uniformly affected by global and cell type-specific knockout of MAGL. Additionally, MAGL global knockout, but not cell type-specific knockout, caused tonic activation and partial desensitization of the CB1 receptor at PF-PC synapses. This tonic CB1 activation is mediated by 2-AG since it was blocked by the diacylglycerol lipase inhibitor DO34. Together, these results suggest that both neuronal and astrocytic MAGL contribute to 2-AG clearance and prevent CB1 receptor over-stimulation in the cerebellum. PMID:27775008

  5. Effect of benzene on the cerebellar structure and behavioral characteristics in rats

    Institute of Scientific and Technical Information of China (English)

    Ali Rafati; Mahboobeh Erfanizadeh; Ali Noorafshan; Saied Karbalay-Doust

    2015-01-01

    Objective:To investigate the effects of benzene on rat’s cerebellum structure and behavioral characteristics, including anxiety and motor impairment. Methods:Twenty rats were randomly allocated into two groups orally receiving distilled water and benzene (200 mg/kg/day). A total of 10 rats were used at the beginning of benzene exposure. Two rats died during benzene treatment and 8 rats remained for evaluation of the behavioral test and finally 6 rats underwent histological assessment. At the end of the 4th week, motor function and anxiety were evaluated in rotarod test and elevated plus maze, respectively. Besides, the cerebellum was dissected for structural assessment using stereological methods. Results:Performance of the benzene-treated rats in fixed and accelerating speed rotarod was impaired and their riding time (endurance) was lower compared to the control group (P=0.02). The benzene-treated rats also spent less time in the open arms and had fewer entrances to the open arms in comparison to the control group, indicating anxiety (P=0.01). The total volume of the cerebellar hemisphere, its cortex, intracerebellar nuclei, total number of the Purkinje, Bergmann, Golgi, granule, neurons and glial cells of the molecular layer, and neurons and glial cells of the intracerebellar nuclei were reduced by 34%-76%in the benzene-treated rats in comparison to the distilled water group (P=0.003). The most cell loss was seen in Bergmann glia. Conclusions:The structure of cerebellum altered after benzene treatment. In addition, motor impairment and anxiety could be seen in benzene-treated rats.

  6. Effect of benzene on the cerebellar structure and behavioral characteristics in rats

    Institute of Scientific and Technical Information of China (English)

    Ali; Rafati; Mahboobeh; Erfanizadeh; Ali; Noorafshan; Saied; Karbalay-Doust

    2015-01-01

    Objective: To investigate the effects of benzene on rat’s cerebellum structure and behavioral characteristics, including anxiety and motor impairment.Methods: Twenty rats were randomly allocated into two groups orally receiving distilled water and benzene(200 mg/kg/day). A total of 10 rats were used at the beginning of benzene exposure. Two rats died during benzene treatment and 8 rats remained for evaluation of the behavioral test and finally 6 rats underwent histological assessment. At the end of the 4th week, motor function and anxiety were evaluated in rotarod test and elevated plus maze, respectively. Besides, the cerebellum was dissected for structural assessment using stereological methods.Results: Performance of the benzene-treated rats in fixed and accelerating speed rotarod was impaired and their riding time(endurance) was lower compared to the control group(P = 0.02). The benzene-treated rats also spent less time in the open arms and had fewer entrances to the open arms in comparison to the control group, indicating anxiety(P = 0.01). The total volume of the cerebellar hemisphere, its cortex, intracerebellar nuclei, total number of the Purkinje, Bergmann, Golgi, granule, neurons and glial cells of the molecular layer, and neurons and glial cells of the intracerebellar nuclei were reduced by 34%-76% in the benzene-treated rats in comparison to the distilled water group(P = 0.003). The most cell loss was seen in Bergmann glia. Conclusions: The structure of cerebellum altered after benzene treatment. In addition, motor impairment and anxiety could be seen in benzene-treated rats.

  7. Stereological study of the effects of maternal diabetes on cerebellar cortex development in rat.

    Science.gov (United States)

    Hami, Javad; Vafaei-Nezhad, Saeed; Ghaemi, Kazem; Sadeghi, Akram; Ivar, Ghasem; Shojae, Fatemeh; Hosseini, Mehran

    2016-06-01

    Diabetes during pregnancy is associated with the deficits in balance and motor coordination and altered social behaviors in offspring. In the present study, we have investigated the effect of maternal diabetes and insulin treatment on the cerebellar volume and morphogenesis of the cerebellar cortex of rat neonates during the first two postnatal weeks. Sprague Dawley female rats were maintained diabetic from a week before pregnancy through parturition. At the end of pregnancy, the male offspring euthanized on postnatal days (P) 0, 7, and 14. Cavalieri's principle and fractionator methods were used to estimate the cerebellar volume, the thickness and the number of cells in the different layers of the cerebellar cortex. In spite of P0, there was a significant reduction in the cerebellar volume and the thickness of the external granule, molecular, and internal granule layers between the diabetic and the control animals. In diabetic group, the granular and purkinje cell densities were increased at P0. Moreover, the number of granular and purkinje cells in the cerebellum of diabetic neonates was reduced in comparison with the control group at P7 and P14. There were no significant differences in either the volume and thickness or the number of cells in the different layers of the cerebellar cortex between the insulin-treated diabetic group and controls. Our data indicate that diabetes in pregnancy disrupts the morphogenesis of cerebellar cortex. This dysmorphogenesis may be part of the cascade of events through which diabetes during pregnancy affects motor coordination and social behaviors in offspring. PMID:26842601

  8. RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of Machado-Joseph disease.

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    Clévio Nóbrega

    Full Text Available Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA-specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease.

  9. Oxidative injury in multiple sclerosis cerebellar grey matter.

    Science.gov (United States)

    Kemp, Kevin; Redondo, Juliana; Hares, Kelly; Rice, Claire; Scolding, Neil; Wilkins, Alastair

    2016-07-01

    Cerebellar dysfunction is a significant contributor to disability in multiple sclerosis (MS). Both white matter (WM) and grey matter (GM) injury occurs within MS cerebellum and, within GM, demyelination, inflammatory cell infiltration and neuronal injury contribute to on-going pathology. The precise nature of cerebellar GM injury is, however, unknown. Oxidative stress pathways with ultimate lipid peroxidation and cell membrane injury occur extensively in MS and the purpose of this study was to investigate these processes in MS cerebellar GM. Post-mortem human cerebellar GM from MS and control subjects was analysed immunohistochemically, followed by semi-quantitative analysis of markers of cellular injury, lipid peroxidation and anti-oxidant enzyme expression. We have shown evidence for reduction in myelin and neuronal markers in MS GM, coupled to an increase in expression of a microglial marker. We also show that the lipid peroxidation product 4-hydroxynonenal co-localises with myelin and its levels negatively correlate to myelin basic protein levels. Furthermore, superoxide dismutase (SOD1 and 2) enzymes, localised within cerebellar neurons, are up-regulated, yet the activation of subsequent enzymes responsible for the detoxification of hydrogen peroxide, catalase and glutathione peroxidase are relatively deficient. These studies provide evidence for oxidative injury in MS cerebellar GM and further help define disease mechanisms within the MS brain. PMID:27086975

  10. Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

    Science.gov (United States)

    Ferdinandusse, Sacha; Zomer, Anna W M; Komen, Jasper C; van den Brink, Christina E; Thanos, Melissa; Hamers, Frank P T; Wanders, Ronald J A; van der Saag, Paul T; Poll-The, Bwee Tien; Brites, Pedro

    2008-11-18

    Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.

  11. Curcumin alters motor coordination but not total number of Purkinje cells in the cerebellum of adolescent male Wistar rats

    Institute of Scientific and Technical Information of China (English)

    Ginus Partadiredja; Sutarman; Taufik Nur Yahya; Christiana Tri Nuryana; Rina Susilowati

    2013-01-01

    OBJECTIVE:The present study aimed at investigating the effects of curcumin on the motor coordination and the estimate of the total number of cerebellar Purkinje cells of adolescent Wistar rats exposed to ethanol.METHODS:The total of 21 male Wistar rats aged 37 d old were divided into three groups,namely ethanol,ethanol-curcumin,and control groups.The ethanol group received 1.5 g/kg ethanol injected intraperitoneally and water given per oral; the ethanol-curcumin group received 1.5 g/kg ethanol injected intraperitoneally and curcumin extract given per oral; the control group received saline injection and oral water.The treatment was carried out daily for one month,after which the motor coordination performance of the rats was examined using revolving drum apparatus at test days 1,8,and 15.The rats were finally sacrificed and the cerebellum of the rats was further processed for stereological analysis.The estimate of the total number of Purkinje cells was calculated using physical fractionator method.RESULTS:The ethanol-curcumin group performed better than both ethanol and control groups in the motor coordination ability at day 8 of testing (P< 0.01).No Purkinje cell loss was observed as a result of one month intraperitoneal injection of ethanol.CONCLUSION:Curcumin may exert beneficial effects on the motor coordination of adolescent rats exposed to ethanol via undetermined hormetic mechanisms.

  12. Localizing genes to cerebellar layers by classifying ISH images.

    Directory of Open Access Journals (Sweden)

    Lior Kirsch

    Full Text Available Gene expression controls how the brain develops and functions. Understanding control processes in the brain is particularly hard since they involve numerous types of neurons and glia, and very little is known about which genes are expressed in which cells and brain layers. Here we describe an approach to detect genes whose expression is primarily localized to a specific brain layer and apply it to the mouse cerebellum. We learn typical spatial patterns of expression from a few markers that are known to be localized to specific layers, and use these patterns to predict localization for new genes. We analyze images of in-situ hybridization (ISH experiments, which we represent using histograms of local binary patterns (LBP and train image classifiers and gene classifiers for four layers of the cerebellum: the Purkinje, granular, molecular and white matter layer. On held-out data, the layer classifiers achieve accuracy above 94% (AUC by representing each image at multiple scales and by combining multiple image scores into a single gene-level decision. When applied to the full mouse genome, the classifiers predict specific layer localization for hundreds of new genes in the Purkinje and granular layers. Many genes localized to the Purkinje layer are likely to be expressed in astrocytes, and many others are involved in lipid metabolism, possibly due to the unusual size of Purkinje cells.

  13. Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse

    Science.gov (United States)

    Sekiguchi, M.; Abe, H.; Moriya, M.; Tanaka, O.; Nowakowski, R. S.

    1998-01-01

    The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1-CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1.

  14. 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6.

    Science.gov (United States)

    Jayabal, Sriram; Chang, Hui Ho Vanessa; Cullen, Kathleen E; Watt, Alanna J

    2016-01-01

    Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA6(84Q/+)) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA6(84Q/84Q)) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA6(84Q/84Q) mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6. PMID:27381005

  15. Protective effects of genistein against apoptosis induced by acrylamide in cultured rat cerebellar granule neurons%三羟异黄酮对丙烯酰胺诱导大鼠小脑颗粒神经元凋亡的保护作用

    Institute of Scientific and Technical Information of China (English)

    周礼华; 徐淑秀; 江城梅

    2011-01-01

    OBJECTIVE: To investigate the protective effects of genistein on apoptosis of rat cerebellar granule neurons induced by acrylamide. METHODS: Rat cerebellar granule neurons were prepared from the cerebellar cortex cells of 5-7day-old SD rats pups. The neurons were identified by Nissl staining method.The 8-day cultured cells passage were divided randomly into control group, acrylamide model group, genistein pretreatment group Ⅰ ,Ⅱ , Ⅲ (cerebellar granule neurons were pretreated with 10,25,50 μ mol/L genistein for 12 hours,the culture medium discarded and fresh DMEM/F12 solution added with the above mentioned concentration of genistein with 10 mmol/L acrylamide tocultured neurons for 24 hours). The neuronal viability was measured by MTT. Morphology of neurons and their nuclei were examined by phase-contrast and Hochest33342 staining,respectively. The ratio of apoptotic cells was detected by TUNEL.RESULTS: The cell survival rates of genistein pretreatment group Ⅱ and Ⅲ were not significantly higher than acrylamide model group. Genistein pretreatment group Ⅰ significantly prolonged the cell survival rate. The effects of diminished neuronal body, chromatin concentration and the ratio of apoptotic cells induced by acrylamide were markedly weakened.CONCLUSION: Genistein did not show a dose-dependent effect on protection. The appropriate concentration of 10 μ mol/L was found to protect against apoptosis induced by acrylamide in primary culture of cerebellar granule neurons.%目的:探讨三羟异黄酮(genistein,GEN)对丙烯酰胺(acrylamide,ACR)诱导的大鼠小脑颗粒神经元凋亡的保护作用.方法:取新生5~7 d的SD大鼠小脑皮质细胞进行培养,采用尼氏染色法鉴定神经元,将培养8 d的神经元随机分成5组:正常对照组、ACR染毒组(浓度为10mmol/L)以及CEN不同浓度保护组(染毒前分别用浓度为10、25、50μmol/L的GEN预先处理细胞12h,再给予ACR染毒24 h).MTT法检测细胞

  16. Role of astrocytes in depolarization-coupled release of glutamate in cerebellar cultures

    DEFF Research Database (Denmark)

    Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

    2004-01-01

    Release of preloaded D-[3H]aspartate in response to depolarization induced by high potassium, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or the endogenous agonist glutamate was studied using cultured glutamatergic cerebellar granule neurons, cerebellar...

  17. Cerebellar liponeurocytoma: a case-report

    Directory of Open Access Journals (Sweden)

    K.V. Sreedhar Babu

    Full Text Available Cerebellar liponeurocytoma is a rare cerebellar neoplasm of adults with advanced neuronal / neurocytic and focal lipomatous differentiation, a low proliferative potential and a favorable clinical prognosis corresponding to World Health Organization grade I or II. Only a few cases have been described in the literature (approximately 20 cases by different names. A 48-years old female, presented with history of headache and dizziness associated with neck pain; restricted neck movements, drop attacks and occasional regurgitation of food since one year. Magnetic resonance imaging disclosed a right cerebellar mass lesion. Gross total resec- tion of the tumour was accomplished through a suboccipital craniotomy. The excised tissue was diagnosed as cerebellar liponeurocytoma, a rare entity, based on histopathological examination and immunohistochemistry. The morphological appearance of this neoplasm can be confused with that of oligodendroglioma, neurocytoma, ependymoma, medulloblastoma, solid hemangioblastoma and metastatic carcinomas etc., with unpredictable prognosis, which require postoperative radiotherapy, hence the importance of accurately diagnosing this rare neoplasm. This tumour should be added to the differential diagnosis of mass lesions of the posterior fossa.

  18. The Neuroprotective Effect of Lithium in cannabinoid Dependence is Mediated through Modulation of Cyclic AMP, ERK1/2 and GSK-3β Phosphorylation in Cerebellar Granular Neurons of Rat

    Science.gov (United States)

    Rahimi, Hamid Reza; Ghahremani, Mohammad Hossein; Dehpour, Ahmad Reza; Sharifzadeh, Mohammad; Ejtemaei-Mehr, Shahram; Razmi, Ali; Ostad, Seyed Nasser

    2015-01-01

    Lithium (Li), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has used to attenuate the cannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this are unclear. Recent studies indicate the involvement of upstream extracellular signal kinase1/2 (ERK1/2) and downstream GSK-3β pathways in the development of cannabinoid-induced dependence. This is mediated through cannabinoid receptor 1 (CB1) enriched in cerebellar granular neurons (CGNs). Accordingly, the present study aimed to investigate the mechanism of modulatory/neuroprotective effects of Li on a cannabinoid agonist (WIN 55,212-2 (WIN))-induced dependence, through quantitative analysis of some involved proteins such as ERK1/2, GSK-3β and related signaling pathways including their phosphorylated forms; and cAMP level as the other molecular mechanisms leading to dependence, in CGNs model. The CGNs were prepared from 7-day-old Wistar rat pup in a 12-well plate, pretreated with Li (1mM) and an ERK1/2 inhibitor SL327 (SL, 10 µM). The WIN (1 µM) was added 30 minutes prior to treatment and AM251 (AM, 1 µM), as a cannabinoid antagonist was co-treated with WIN. The cAMP level, as an indicator of cannabinoid-induced dependence, was measured by ELISA following forskolin (FSK) stimulation. Western blot analyses determined the phosphorylated forms of ERK1/2 (p-ERK1/2), GSK-3β (p-GSK-3β) as well as their total expressions in various treatment times and doses in CGNs. WIN alone could down regulate the cAMP/p-ERK1/2 cascade compared to AM treatment. However, P-GSK-3β was up-regulated with Li and WIN or with SL and Li pretreatment to AM-induced cellular response, which was the highest 60 minutes after CGNs exposure. Results further suggested the potential role of Li pretreatment to diminish the development of cannabinoid-induced dependence/neuronal injury through possible mechanisms of modulating the cAMP/p-ERK1/2 cascade independent of p-GSK-3β signaling pathway in-vitro. PMID:26664379

  19. Effect of orphan nuclear receptor NR4A1 expression on oxygen-glucose deprivation-induced apoptosis in cultured rots cerebellar granule neurons%孤儿核受体NR4A1表达对氧-葡萄糖剥夺诱导培养大鼠小脑颗粒神经元凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    肖国栋; 成松明; 孙涛; 曹勇军

    2013-01-01

    Objective To investigate the effect of orphan nuclear receptor NR4A1 expression on oxygenglucose deprivation (OGD)-induced apoptosis in cultured rat cerebellar granule neurons and its possible mechanisms.Methods Primary rat cerebellar granule neurons were cultured for 7 to 8 days,and then treated with OGD.The activity of cultured rat cerebellar granule neurons was assessed by methyl thiazolyl tetrazolium (MTT) assay,apoptosis was detected with flow cytometry,the expressions of NR4A1,caspase-3 and cytochrome c were determined by Western blot analysis,NR4A1 mRNA expression was detected with real-time polymerase chain reaction.The rat cerebellar granule neurons were transfected with lentiviral vector-encoding rat NR4A1.The apoptotic rates and expressions of caspase-3 and cytochrome c in rat cerebellar granule neurons transfected with NR4A1 were detected after OGD.Results The activity of rat cerebellar granule neurons decreased significantly,the apoptotic rate increased significantly,the expressions of NR4A1 mRNA and protein as well as caspase-3 and cytochrome c incrased significantly along with the OGD time.NR4A1 was overexpressed,apoptosis rate was significantly reduced in rat cerebellar granule neurons transfected with NR4A1.The expressions of caspase-3 and cytochrome c were significantly reduced in the rat cerebellar granule neurons transfected with NR4A1 after OGD.Conclusions NR4A1 overexpression may reduce OGD-induced apoptosis in rat cerebellar granule neurons by downregulating the expressions of caspase-3 and cytochrome c.%目的 探讨孤儿核受体NR4A1表达对氧-葡萄糖剥夺(oxy gen-glucose deprivation,OGD)诱导培养大鼠小脑颗粒神经元凋亡的影响及其可能机制.方法 大鼠小脑颗粒细胞原代培养7~8 d后给予OGD处理.应用四甲基偶氮唑蓝法检测细胞活性,流式细胞术检测细胞凋亡率,蛋白质印迹法检测NR4A1、胱天蛋白酶-3和细胞色素c蛋白表达,实时定量聚合酶链反应检测NR4A1m

  20. Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer’s disease rats

    OpenAIRE

    Lee, Jae-Min; Shin, Mal-Soon; Ji, Eun-Sang; Kim, Tae-Woon; Cho, Han-Sam; Kim, Chang-Ju; Jang, Myung-Soo; Kim, Tae-Wook; Kim, Bo-Kyun; Kim, Dong-Hee

    2014-01-01

    Alzheimer’s disease (AD) is a most common age-related neurodegenerative disease. AD is characterized by a progressive loss of neurons causing cognitive dysfunction. The cerebellum is closely associated with integration of movement, including motor coordination, control, and equilibrium. In the present study, we evaluated the effect of tread-mill exercise on the survival of Purkinje neurons in relation with reactive astrocyte in the cerebellum using Aβ25–35–induced AD rats. AD was induced by a...

  1. Neuropathological features in a female fetus with OPHN1 deletion and cerebellar hypoplasia.

    Science.gov (United States)

    Rocas, Delphine; Alix, Eudeline; Michel, Jessica; Cordier, Marie-Pierre; Labalme, Audrey; Guilbert, Hélène; Till, Marianne; Schluth-Bolard, Caroline; de Haas, Pascale; Massardier, Jérôme; Portes, Vincent des; Edery, Patrick; Touraine, Renaud; Guibaud, Laurent; Vasiljevic, Alexandre; Sanlaville, Damien

    2013-05-01

    We report the case of a 33-year-old pregnant woman. The third-trimester ultrasound scan during pregnancy revealed fetal bilateral ventricular dilatation, macrosomia and a transverse diameter of the cerebellum at the 30th centile. A brain MRI scan at 31 weeks of gestation led to a diagnosis of hypoplasia of the cerebellar vermis without hemisphere abnormalities and a non compressive expansion of the cisterna magna. The fetal karyotype was 46,XX. The pregnancy was terminated and array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of OPHN1 gene. Further studies revealed a completely skewed pattern of X inactivation. OPHN1 is involved in X-linked mental retardation (XLMR) with cerebellar hypoplasia and encodes a Rho-GTPase-activating protein called oligophrenin-1, which is produced throughout the developing mouse brain and in the hippocampus and Purkinje cells of the cerebellum in adult mice. Neuropathological examination of the female fetus revealed cerebellar hypoplasia and the heterotopia of Purkinje cells at multiple sites in the white matter of the cerebellum. This condition mostly affects male fetuses in humans. We report here the first case of a de novo partial deletion of OPHN1, with radiological and neuropathological examination, in a female fetus. PMID:23416624

  2. Lissencephaly and cerebellar hypoplasia in a goat

    Directory of Open Access Journals (Sweden)

    José Rômulo Soares dos Santos

    2013-10-01

    Full Text Available A case of lissencephaly and cerebellar hypoplasia was observed in a 30-day-old goat. The goat presented with sternal recumbence, absence of a menace response, intention tremors, ataxia, and nystagmus. The goat was euthanized and necropsied after having been hospitalised for eleven days. At necropsy, the surface of the brain was found to be smooth, the cerebral sulci and gyri were absent, and the cerebellum was reduced in size. Histologically, the grey matter and white matter were thicker and thinner than normal in cortices, respectively. The neurons were randomly arranged in the grey matter. In the cerebellum, the layers were disorganised, and cells were heterotopics. The histologic and gross lesions observed in this animal are characteristic of lissencephaly associated with cerebellar hypoplasia. The presence of a single goat affected suggests that the malformation was not of infectious origin and because lissencephaly is a malformation not previously described in goats, it is unlikely this case was inherited.

  3. Cerebellar anatomy as applied to cerebellar microsurgical resections

    Directory of Open Access Journals (Sweden)

    Alejandro Ramos

    2012-06-01

    Full Text Available OBJECTIVE: To define the anatomy of dentate nucleus and cerebellar peduncles, demonstrating the surgical application of anatomic landmarks in cerebellar resections. METHODS: Twenty cerebellar hemispheres were studied. RESULTS: The majority of dentate nucleus and cerebellar peduncles had demonstrated constant relationship to other cerebellar structures, which provided landmarks for surgical approaching. The lateral border is separated from the midline by 19.5 mm in both hemispheres. The posterior border of the cortex is separated 23.3 mm from the posterior segment of the dentate nucleus; the lateral one is separated 26 mm from the lateral border of the nucleus; and the posterior segment of the dentate nucleus is separated 25.4 mm from the posterolateral angle formed by the junction of lateral and posterior borders of cerebellar hemisphere. CONCLUSIONS: Microsurgical anatomy has provided important landmarks that could be applied to cerebellar surgical resections.

  4. Cerebellar output controls generalized spike-and-wave discharge occurrence

    NARCIS (Netherlands)

    L. Kros (Lieke); S.J. Eelkman Rooda; J.K. Spanke (Jochen); P. Alva (Parimala); M. van Dongen (Marijn); A. Karapatis (Athanasios); E.A. Tolner (Else A.); C. Strydis (Christos); N. Davey (Neil); B.H.J. Winkelman (Beerend); M. Negrello (Mario); W. Serdijn (Wouter); V. Steuber (Volker); A.M.J.M. Maagdenberg (Arn); C.I. de Zeeuw (Chris); F.E. Hoebeek (Freek)

    2015-01-01

    textabstractObjective Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are a

  5. Cerebellar Output Controls Generalized Spike-and-Wave Discharge Occurrence

    NARCIS (Netherlands)

    Kros, L.; Eelkman Rooda, O.H.J.; Spanke, J.K.; Alva, P.; Van Dongen, M.N.; Karapatis, A.; Tolner, E.A.; Strydis, C.; Davey, N.; Winkelman, B.H.J.; Negrello, M.; Serdijn, W.A.; Steuber, V.; Van den Maagdenberg, A.M.J.M.; De Zeeuw, C.I.; Hoebeek, F.E.

    2015-01-01

    Objective Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically

  6. Cerebellar output controls generalized spike-and-wave discharge occurrence

    NARCIS (Netherlands)

    Kros, Lieke; Eelkman Rooda, Oscar H J; Spanke, Jochen K; Alva, Parimala; van Dongen, Marijn N; Karapatis, Athanasios; Tolner, Else A; Strydis, Christos; Davey, Neil; Winkelman, Beerend H J; Negrello, Mario; Serdijn, Wouter A; Steuber, Volker; van den Maagdenberg, Arn M J M; De Zeeuw, Chris I; Hoebeek, Freek E

    2015-01-01

    OBJECTIVE: Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically

  7. A bi-hemispheric neuronal network model of the cerebellum with spontaneous climbing fiber firing produces asymmetrical motor learning during robot control

    Science.gov (United States)

    Pinzon-Morales, Ruben-Dario; Hirata, Yutaka

    2014-01-01

    To acquire and maintain precise movement controls over a lifespan, changes in the physical and physiological characteristics of muscles must be compensated for adaptively. The cerebellum plays a crucial role in such adaptation. Changes in muscle characteristics are not always symmetrical. For example, it is unlikely that muscles that bend and straighten a joint will change to the same degree. Thus, different (i.e., asymmetrical) adaptation is required for bending and straightening motions. To date, little is known about the role of the cerebellum in asymmetrical adaptation. Here, we investigate the cerebellar mechanisms required for asymmetrical adaptation using a bi-hemispheric cerebellar neuronal network model (biCNN). The bi-hemispheric structure is inspired by the observation that lesioning one hemisphere reduces motor performance asymmetrically. The biCNN model was constructed to run in real-time and used to control an unstable two-wheeled balancing robot. The load of the robot and its environment were modified to create asymmetrical perturbations. Plasticity at parallel fiber-Purkinje cell synapses in the biCNN model was driven by error signal in the climbing fiber (cf) input. This cf input was configured to increase and decrease its firing rate from its spontaneous firing rate (approximately 1 Hz) with sensory errors in the preferred and non-preferred direction of each hemisphere, as demonstrated in the monkey cerebellum. Our results showed that asymmetrical conditions were successfully handled by the biCNN model, in contrast to a single hemisphere model or a classical non-adaptive proportional and derivative controller. Further, the spontaneous activity of the cf, while relatively small, was critical for balancing the contribution of each cerebellar hemisphere to the overall motor command sent to the robot. Eliminating the spontaneous activity compromised the asymmetrical learning capabilities of the biCNN model. Thus, we conclude that a bi

  8. A bi-hemispheric neuronal network model of the cerebellum with spontaneous climbing fiber firing produces asymmetrical motor learning during robot control.

    Science.gov (United States)

    Pinzon-Morales, Ruben-Dario; Hirata, Yutaka

    2014-01-01

    To acquire and maintain precise movement controls over a lifespan, changes in the physical and physiological characteristics of muscles must be compensated for adaptively. The cerebellum plays a crucial role in such adaptation. Changes in muscle characteristics are not always symmetrical. For example, it is unlikely that muscles that bend and straighten a joint will change to the same degree. Thus, different (i.e., asymmetrical) adaptation is required for bending and straightening motions. To date, little is known about the role of the cerebellum in asymmetrical adaptation. Here, we investigate the cerebellar mechanisms required for asymmetrical adaptation using a bi-hemispheric cerebellar neuronal network model (biCNN). The bi-hemispheric structure is inspired by the observation that lesioning one hemisphere reduces motor performance asymmetrically. The biCNN model was constructed to run in real-time and used to control an unstable two-wheeled balancing robot. The load of the robot and its environment were modified to create asymmetrical perturbations. Plasticity at parallel fiber-Purkinje cell synapses in the biCNN model was driven by error signal in the climbing fiber (cf) input. This cf input was configured to increase and decrease its firing rate from its spontaneous firing rate (approximately 1 Hz) with sensory errors in the preferred and non-preferred direction of each hemisphere, as demonstrated in the monkey cerebellum. Our results showed that asymmetrical conditions were successfully handled by the biCNN model, in contrast to a single hemisphere model or a classical non-adaptive proportional and derivative controller. Further, the spontaneous activity of the cf, while relatively small, was critical for balancing the contribution of each cerebellar hemisphere to the overall motor command sent to the robot. Eliminating the spontaneous activity compromised the asymmetrical learning capabilities of the biCNN model. Thus, we conclude that a bi

  9. Visualizing the distribution of synapses from individual neurons in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Ling Li

    Full Text Available BACKGROUND: Proper function of the mammalian brain relies on the establishment of highly specific synaptic connections among billions of neurons. To understand how complex neural circuits function, it is crucial to precisely describe neuronal connectivity and the distributions of synapses to and from individual neurons. METHODS AND FINDINGS: In this study, we present a new genetic synaptic labeling method that relies on expression of a presynaptic marker, synaptophysin-GFP (Syp-GFP in individual neurons in vivo. We assess the reliability of this method and use it to analyze the spatial patterning of synapses in developing and mature cerebellar granule cells (GCs. In immature GCs, Syp-GFP is distributed in both axonal and dendritic regions. Upon maturation, it becomes strongly enriched in axons. In mature GCs, we analyzed synapses along their ascending segments and parallel fibers. We observe no differences in presynaptic distribution between GCs born at different developmental time points and thus having varied depths of projections in the molecular layer. We found that the mean densities of synapses along the parallel fiber and the ascending segment above the Purkinje cell (PC layer are statistically indistinguishable, and higher than previous estimates. Interestingly, presynaptic terminals were also found in the ascending segments of GCs below and within the PC layer, with the mean densities two-fold lower than that above the PC layer. The difference in the density of synapses in these parts of the ascending segment likely reflects the regional differences in postsynaptic target cells of GCs. CONCLUSIONS: The ability to visualize synapses of single neurons in vivo is valuable for studying synaptogenesis and synaptic plasticity within individual neurons as well as information flow in neural circuits.

  10. Localization of CGRP receptor components, CGRP, and receptor binding sites in human and rhesus cerebellar cortex

    DEFF Research Database (Denmark)

    Eftekhari, Sajedeh; Salvatore, Christopher A; Gaspar, Renee C;

    2013-01-01

    receptor activity modifying protein 1 (RAMP1), was examined. In addition, expression of procalcitonin was studied. We observed high [(3)H]MK-3207 (CGRP receptor antagonist) binding densities in the molecular layer of rhesus cerebellar cortex; however, due to the limit of resolution of the autoradiographic....... Immunofluorescence revealed expression of CGRP, CLR, and RAMP1 in the Purkinje cells and in cells in the molecular layer. Procalcitonin was found in the same localization. Recent research in the biology of cerebellum indicates that it may have a role in nociception. For the first time we have identified CGRP and...

  11. Silent synapses, LTP, and the indirect parallel-fibre pathway: computational consequences of optimal cerebellar noise-processing.

    Directory of Open Access Journals (Sweden)

    John Porrill

    2008-05-01

    Full Text Available Computational analysis of neural systems is at its most useful when it uncovers principles that provide a unified account of phenomena across multiple scales and levels of description. Here we analyse a widely used model of the cerebellar contribution to sensori-motor learning to demonstrate both that its response to intrinsic and sensor noise is optimal, and that the unexpected synaptic and behavioural consequences of this optimality can explain a wide range of experimental data. The response of the Marr-Albus adaptive-filter model of the cerebellar microcircuit to noise was examined in the context of vestibulo-ocular reflex calibration. We found that, when appropriately connected, an adaptive-filter model using the covariance learning rule to adjust the weights of synapses between parallel fibres and Purkinje cells learns weight values that are optimal given the relative amount of signal and noise carried by each parallel fibre. This optimality principle is consistent with data on the cerebellar role in smooth pursuit eye movements, and predicts that many synaptic weights must be very small, providing an explanation for the experimentally observed preponderance of silent synapses. Such a preponderance has in its turn two further consequences. First, an additional inhibitory pathway from parallel fibre to Purkinje cell is required if Purkinje cell activity is to be altered in either direction from a starting point of silent synapses. Second, cerebellar learning tasks must often proceed via LTP, rather than LTD as is widely assumed. Taken together, these considerations have profound behavioural consequences, including the optimal combination of sensori-motor information, and asymmetry and hysteresis of sensori-motor learning rates.

  12. Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD.

    Science.gov (United States)

    Reynolds, T; Hartell, N A

    2001-01-22

    In cerebellar slices conjunctive pairing of parallel fibre (PF) stimulation with depolarization of Purkinje cells (PCs) induces a long-term depression (LTD) of PF synaptic transmission that spreads to unpaired PF inputs to the same cell. Inhibitors of NO synthase (7-nitro-indazole), soluble guanylate cyclase (ODQ) and PKG (KT5823) all prevented depression at each of two independent PF pathways to a single PC. Inhibition of NOS also unmasked a platelet activating factor (PAF)-mediated synaptic potentiation of possible presynaptic origin. LTD was also prevented by the phospholipase A2 inhibitor OBAA but was rescued by co-perfusion with arachidonic acid. We conclude that NO and diffusible products of phospholipase A2 metabolism are potential mediators of the spread of cerebellar plasticity at the single cell level. PMID:11201073

  13. Memory consolidation in the cerebellar cortex.

    Directory of Open Access Journals (Sweden)

    Daniel O Kellett

    Full Text Available Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABAA agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage.

  14. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias

    OpenAIRE

    Mitoma, Hiroshi; Adhikari, Keya; Aeschlimann, Daniel; Chattopadhyay, Partha; Hadjivassiliou, Marios; Hampe, Christiane S.; Honnorat, Jérôme; Joubert, Bastien; Kakei, Shinji; Lee, Jongho; Manto, Mario; Matsunaga, Akiko; Mizusawa, Hidehiro; Nanri, Kazunori; Shanmugarajah, Priya

    2015-01-01

    In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto’s encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Mi...

  15. Neuronal regulation of astroglial morphology and proliferation in vitro

    OpenAIRE

    1985-01-01

    To analyze the interdependence of neurons and astroglia during central nervous system development, a rapid method for purifying early postnatal cerebellar neurons and astroglia, and recombining them in vitro, has been developed. The influence of neurons on astroglial shape and proliferation has been evaluated with an in vitro model system previously used to describe the role of cerebellar astroglia in neuronal migration and positioning (Hatten, M. E., and R. K. H. Liem, 1981, J. Cell Biol., 9...

  16. Emergence of a 600-Hz buzz UP state Purkinje cell firing in alert mice.

    Science.gov (United States)

    Cheron, G; Prigogine, C; Cheron, J; Márquez-Ruiz, J; Traub, R D; Dan, B

    2014-03-28

    Purkinje cell (PC) firing represents the sole output from the cerebellar cortex onto the deep cerebellar and vestibular nuclei. Here, we explored the different modes of PC firing in alert mice by extracellular recording. We confirm the existence of a tonic and/or bursting and quiescent modes corresponding to UP and DOWN state, respectively. We demonstrate the existence of a novel 600-Hz buzz UP state of firing characterized by simple spikes (SS) of very small amplitude. Climbing fiber (CF) input is able to switch the 600-Hz buzz to the DOWN state, as for the classical UP-to-DOWN state transition. Conversely, the CF input can initiate a typical SS pattern terminating into 600-Hz buzz. The 600-Hz buzz was transiently suppressed by whisker pad stimulation demonstrating that it remained responsive to peripheral input. It must not be mistaken for a DOWN state or the sign of PC inhibition. Complex spike (CS) frequency was increased during the 600-Hz buzz, indicating that this PC output actively contributes to the cerebello-olivary loop by triggering a disinhibition of the inferior olive. During the 600-Hz buzz, the first depolarizing component of the CS was reduced and the second depolarizing component was suppressed. Consistent with our experimental observations, using a 559-compartment single-PC model - in which PC UP state (of about -43mV) was obtained by the combined action of large tonic AMPA conductances and counterbalancing GABAergic inhibition - removal of this inhibition produced the 600-Hz buzz; the simulated buzz frequency decreased following an artificial CS. PMID:24440752

  17. Treadmill exercise ameliorates motor dysfunction through inhibition of Purkinje cell loss in cerebellum of valproic acid-induced autistic rats.

    Science.gov (United States)

    Cho, Han-Sam; Kim, Tae-Woon; Ji, Eun-Sang; Park, Hye-Sang; Shin, Mal-Soon; Baek, Seung-Soo

    2016-08-01

    Autism is a complex developmental disorder with impairments in social interaction, communication, repetitive behavior and motor skills. Exercise enhances cognitive function, ameliorates motor dysfunction, and provides protective profits against neurodegeneration. In the present study, we evaluated the effect of treadmill exercise on the motor coordination and Purkinje cell loss in relation with reactive astrocytes and microglial activation in the cerebellum using valproic acid (VPA)-induced autism rat model. On the 12th day of pregnancy, the pregnant rats in the VPA-exposed group received intraperitoneal injections of 600-mg/kg VPA. After birth, the rat pups were divided into four groups: the control group, the exercise group, the VPA-treated group, the VPA-treated and exercise group. The rat pups in the exercise groups were forced to run on a treadmill for 30 min once a day, 5 times a week for 4 weeks. In the present results, motor balance and coordination was disturbed by induction of autism, in contrast, treadmill exercise alleviated motor dysfunction in the autistic rats. Purkinje cell loss, reactive astrocytes, and microglial activation were occurred by induction of autism, in contrast, treadmill exercise enhanced survival rate of Purkinje neurons through inhibition of reactive astrocytes and microglia in the autistic rats. The present study showed that exercise may provide a potential therapeutic strategy for the alleviation of motor dysfunction in autistic patients. PMID:27656625

  18. Treadmill exercise ameliorates motor dysfunction through inhibition of Purkinje cell loss in cerebellum of valproic acid-induced autistic rats

    Science.gov (United States)

    Cho, Han-Sam; Kim, Tae-Woon; Ji, Eun-Sang; Park, Hye-Sang; Shin, Mal-Soon; Baek, Seung-Soo

    2016-01-01

    Autism is a complex developmental disorder with impairments in social interaction, communication, repetitive behavior and motor skills. Exercise enhances cognitive function, ameliorates motor dysfunction, and provides protective profits against neurodegeneration. In the present study, we evaluated the effect of treadmill exercise on the motor coordination and Purkinje cell loss in relation with reactive astrocytes and microglial activation in the cerebellum using valproic acid (VPA)-induced autism rat model. On the 12th day of pregnancy, the pregnant rats in the VPA-exposed group received intraperitoneal injections of 600-mg/kg VPA. After birth, the rat pups were divided into four groups: the control group, the exercise group, the VPA-treated group, the VPA-treated and exercise group. The rat pups in the exercise groups were forced to run on a treadmill for 30 min once a day, 5 times a week for 4 weeks. In the present results, motor balance and coordination was disturbed by induction of autism, in contrast, treadmill exercise alleviated motor dysfunction in the autistic rats. Purkinje cell loss, reactive astrocytes, and microglial activation were occurred by induction of autism, in contrast, treadmill exercise enhanced survival rate of Purkinje neurons through inhibition of reactive astrocytes and microglia in the autistic rats. The present study showed that exercise may provide a potential therapeutic strategy for the alleviation of motor dysfunction in autistic patients.

  19. A cerebellar neuroprosthetic system: computational architecture and in vivo experiments

    Directory of Open Access Journals (Sweden)

    Ivan eHerreros Alonso

    2014-05-01

    Full Text Available Emulating the input-output functions performed by a brain structure opens the possibility for developing neuro-prosthetic systems that replace damaged neuronal circuits. Here, we demonstrate the feasibility of this approach by replacing the cerebellar circuit responsible for the acquisition and extinction of motor memories. Specifically, we show that a rat can undergo acquisition, retention and extinction of the eye-blink reflex even though the biological circuit responsible for this task has been chemically inactivated via anesthesia. This is achieved by first developing a computational model of the cerebellar microcircuit involved in the acquisition of conditioned reflexes and training it with synthetic data generated based on physiological recordings. Secondly, the cerebellar model is interfaced with the brain of an anesthetized rat, connecting the model's inputs and outputs to afferent and efferent cerebellar structures. As a result, we show that the anesthetized rat, equipped with our neuro-prosthetic system, can be classically conditioned to the acquisition of an eye-blink response. However, non-stationarities in the recorded biological signals limit the performance of the cerebellar model. Thus, we introduce an updated cerebellar model and validate it with physiological recordings showing that learning becomes stable and reliable. The resulting system represents an important step towards replacing lost functions of the central nervous system via neuro-prosthetics, obtained by integrating a synthetic circuit with the afferent and efferent pathways of a damaged brain region. These results also embody an early example of science-based medicine, where on the one hand the neuro-prosthetic system directly validates a theory of cerebellar learning that informed the design of the system, and on the other one it takes a step towards the development of neuro-prostheses that could recover lost learning functions in animals and, in the longer term

  20. Cerebellar development in the absence of Gbx function in zebrafish.

    Science.gov (United States)

    Su, Chen-Ying; Kemp, Hilary A; Moens, Cecilia B

    2014-02-01

    The midbrain-hindbrain boundary (MHB) is a well-known organizing center during vertebrate brain development. The MHB forms at the expression boundary of Otx2 and Gbx2, mutually repressive homeodomain transcription factors expressed in the midbrain/forebrain and anterior hindbrain, respectively. The genetic hierarchy of gene expression at the MHB is complex, involving multiple positive and negative feedback loops that result in the establishment of non-overlapping domains of Wnt1 and Fgf8 on either side of the boundary and the consequent specification of the cerebellum. The cerebellum derives from the dorsal part of the anterior-most hindbrain segment, rhombomere 1 (r1), which undergoes a distinctive morphogenesis to give rise to the cerebellar primordium within which the various cerebellar neuron types are specified. Previous studies in the mouse have shown that Gbx2 is essential for cerebellar development. Using zebrafish mutants we show here that in the zebrafish gbx1 and gbx2 are required redundantly for morphogenesis of the cerebellar primordium and subsequent cerebellar differentiation, but that this requirement is alleviated by knocking down Otx. Expression of fgf8, wnt1 and the entire MHB genetic program is progressively lost in gbx1-;gbx2- double mutants but is rescued by Otx knock-down. This rescue of the MHB genetic program depends on rescued Fgf signaling, however the rescue of cerebellar primordium morphogenesis is independent of both Gbx and Fgf. Based on our findings we propose a revised model for the role of Gbx in cerebellar development.

  1. Cerebellar LTD vs. motor learning-lessons learned from studying GluD2.

    Science.gov (United States)

    Yuzaki, Michisuke

    2013-11-01

    Synaptic plasticity, such as long-term potentiation and long-term depression (LTD), is believed to underlie learning and memory processes in vivo. The cerebellum is an ideal brain region to obtain definitive proof for this hypothesis. The current belief is that the acquisition of motor learning is stored by LTD at the parallel fiber (PF)-Purkinje cell synapse in the cerebellar cortex. Recently, however, several lines of mutant mice that display normal motor learning in the absence of cerebellar LTD have been reported. A similar dichotomy between synaptic plasticity at the circuitry level and learning at the behavioral level has also been reported in the hippocampus. One possible explanation for this dichotomy is that compensatory pathways at the molecular and circuitry levels play an important role in mice that have been genetically modified for their entire lives. Mice that are genetically modified to be deficient in or to express mutant versions of the δ2 glutamate receptor (GluD2) serve as an interesting model due to the predominant expression of GluD2 at PF-Purkinje cell synapses. Furthermore, two major functions of GluD2-PF synapse formation and LTD induction-can be mechanistically dissociated so that the role of LTD in motor learning can be investigated in the absence of morphological abnormalities caused by altered synapse formation. Therefore, genetic manipulations of GluD2 will help to clarify the relationship between LTD and motor learning in the cerebellum.

  2. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

    Science.gov (United States)

    Levite, Mia

    2014-08-01

    .g., chronic progressive limbic Encephalitis, Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis), Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF. Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while others do not. Some of the anti-NMDA-NR2A/B antibodies associate with neuropsychiatric/cognitive/behavior/mood impairments in SLE patients, while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be very pathogenic, since they can kill neurons by activating NMDA receptors and inducing 'Excitotoxicity', damage the brain, cause dramatic decrease of membranal NMDA receptors expressed in hippocampal neurons, and also induce behavioral cognitive impairments in animal models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems to determine if they have positive or negative effects on the activity of glutamate receptors and on the survival of neurons. Thus, at low concentration, the anti-NMDA-NR2A/B antibodies were found to be positive modulators of receptor function and increase the size of NMDA receptor-mediated excitatory postsynaptic potentials, whereas at high concentration they are pathogenic as they promote 'Excitotoxcity' through enhanced mitochondrial permeability transition. (4) Anti-mGluR1 antibodies were found thus far in very few patients with Paraneoplastic Cerebellar Ataxia, and in these patients they are produced intrathecally and therefore present in much higher levels in the CSF than in the serum. The anti-mGluR1 antibodies can be very pathogenic in the brain since they can reduce the basal neuronal activity, block the induction of long-term depression of Purkinje cells, and altogether cause cerebellar motor coordination deficits by a combination of rapid effects on both the acute and the plastic responses of Purkinje cells, and by chronic degenerative effects. Strikingly, within 30 min after injection of anti-mGluR1

  3. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

    Science.gov (United States)

    Levite, Mia

    2014-08-01

    .g., chronic progressive limbic Encephalitis, Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis), Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF. Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while others do not. Some of the anti-NMDA-NR2A/B antibodies associate with neuropsychiatric/cognitive/behavior/mood impairments in SLE patients, while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be very pathogenic, since they can kill neurons by activating NMDA receptors and inducing 'Excitotoxicity', damage the brain, cause dramatic decrease of membranal NMDA receptors expressed in hippocampal neurons, and also induce behavioral cognitive impairments in animal models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems to determine if they have positive or negative effects on the activity of glutamate receptors and on the survival of neurons. Thus, at low concentration, the anti-NMDA-NR2A/B antibodies were found to be positive modulators of receptor function and increase the size of NMDA receptor-mediated excitatory postsynaptic potentials, whereas at high concentration they are pathogenic as they promote 'Excitotoxcity' through enhanced mitochondrial permeability transition. (4) Anti-mGluR1 antibodies were found thus far in very few patients with Paraneoplastic Cerebellar Ataxia, and in these patients they are produced intrathecally and therefore present in much higher levels in the CSF than in the serum. The anti-mGluR1 antibodies can be very pathogenic in the brain since they can reduce the basal neuronal activity, block the induction of long-term depression of Purkinje cells, and altogether cause cerebellar motor coordination deficits by a combination of rapid effects on both the acute and the plastic responses of Purkinje cells, and by chronic degenerative effects. Strikingly, within 30 min after injection of anti-mGluR1

  4. Cerebellar degeneration in neuroleptic malignant syndrome: neuropathologic findings and review of the literature concerning heat-related nervous system injury.

    OpenAIRE

    Lee, S.; Merriam, A; Kim, T. S.; Liebling, M; Dickson, D. W.; Moore, G. R.

    1989-01-01

    A selective subtotal cerebellar neuronal degeneration was found in a patient who died 4 1/2 months after suffering neuroleptic malignant syndrome (NMS), a rare, potentially fatal disorder associated with neuroleptic medications. It is suggested that the cerebellar neuronal degeneration in this case was due to hyperpyrexia, a cardinal clinical feature of NMS. Similar pathologic findings appear not to have been previously reported in NMS but have been described in heat-induced central nervous s...

  5. Cerebellar abnormalities typical of methylmercury poisoning in a fledged saltmarsh sparrow, Ammodramus caudacutus.

    Science.gov (United States)

    Scoville, Sheila A; Lane, Oksana P

    2013-05-01

    A fledged, 12-15 day-old saltmarsh sparrow, Ammodramus caudacutus, was collected from an accidental kill on Cinder Island, Long Island, NY, USA. The sparrow was assessed for feather mercury levels and the brain analyzed for cerebellar abnormalities by microscopic examination. In humans, fetal Minamata disease is caused by maternal ingestion of mercury. It is characterized by disrupted and disordered cerebellar neuronal migration in the fetus or infant. Results from this sparrow show cerebellar abnormalities typical of Minamata disease. It is the first known avian or mammalian specimen taken from the wild to show the abnormalities typical of the human fetal syndrome.

  6. A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation

    OpenAIRE

    Belmeguenai, A.; Hansel, Christian

    2005-01-01

    textabstractCerebellar parallel fiber (PF)-Purkinje cell (PC) synapses can undergo postsynaptically expressed long-term depression (LTD) or long-term potentiation (LTP). PF-LTD induction requires the coactivity of the PF and CF (climbing fiber) inputs to PCs and a concomitant calcium transient and activation of protein kinase C (PKC). PF-LTP can be induced by PF activity alone and requires a lower calcium transient for its induction than PF-LTD. The cellular events triggering PF-LTP induction...

  7. Sleep disorders in cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    José L. Pedroso

    2011-04-01

    Full Text Available Cerebellar ataxias comprise a wide range of etiologies leading to central nervous system-related motor and non-motor symptoms. Recently, a large body of evidence has demonstrated a high frequency of non-motor manifestations in cerebellar ataxias, specially in autosomal dominant spinocerebellar ataxias (SCA. Among these non-motor dysfunctions, sleep disorders have been recognized, although still under or even misdiagnosed. In this review, we highlight the main sleep disorders related to cerebellar ataxias focusing on REM sleep behavior disorder (RBD, restless legs syndrome (RLS, periodic limb movement in sleep (PLMS, excessive daytime sleepiness (EDS, insomnia and sleep apnea.

  8. A bi-hemispheric neuronal network model of the cerebellum with spontaneous climbing fiber firing produces asymmetrical motor learning during robot control

    Directory of Open Access Journals (Sweden)

    Ruben Dario Pinzon Morales

    2014-11-01

    Full Text Available To acquire and maintain precise movement controls over a lifespan, changes in the physical and physiological characteristics of muscles must be compensated for adaptively. The cerebellum plays a crucial role in such adaptation. Changes in muscle characteristics are not always symmetrical. For example, it is unlikely that muscles that bend and straighten a joint will change to the same degree. Thus, different (i.e., asymmetrical adaptation is required for bending and straightening motions. To date, little is known about the role of the cerebellum in asymmetrical adaptation. Here, we investigate the cerebellar mechanisms required for asymmetrical adaptation using a bi-hemispheric cerebellar neuronal network model (biCNN. The bi-hemispheric structure is inspired by the observation that lesioning one hemisphere reduces motor performance asymmetrically. The biCNN model was constructed to run in real-time and used to control an unstable two-wheeled balancing robot. The load of the robot and its environment were modified to create asymmetrical perturbations. Plasticity at parallel fiber-Purkinje cell synapses in the biCNN model was driven by error signal in the climbing fiber (cf input. This cf input was configured to increase and decrease its firing rate from its spontaneous firing rate (approximately 1 Hz with sensory errors in the preferred and non-preferred direction of each hemisphere, as demonstrated in the monkey cerebellum. Our results showed that asymmetrical conditions were successfully handled by the biCNN model, in contrast to a single hemisphere model or a classical non-adaptive proportional and derivative controller. Further, the spontaneous activity of the cf, while relatively small, was critical for balancing the contribution of each cerebellar hemisphere to the overall motor command sent to the robot. Eliminating the spontaneous activity compromised the asymmetrical learning capabilities of the biCNN model. Thus, we conclude that a bi

  9. Metastatic cerebellar tumor of papillary thyroid carcinoma mimicking cerebellar hemangioblastoma

    OpenAIRE

    Ideguchi, Makoto; Nishizaki, Takafumi; Ikeda, Norio; Nakano, Shigeki; Okamura, Tomomi; Fujii, Natsumi; Kimura, Tokuhiro; Ikeda, Eiji

    2016-01-01

    Introduction Well-differentiated papillary thyroid carcinoma generally (PTC) have a favorable prognosis. This metastasis is rare in the central nervous system. Brain metastasis has a relatively poor prognosis. We present a rare case of cerebellar metastasis, one that mimics a solid type cerebellar hemangioblastoma and because of which it was very hard to reach accurate preoperative diagnosis. Accurate diagnosis was challenging because of the similar imaging and histopathological findings for ...

  10. Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination.

    Science.gov (United States)

    Rosin, Jessica M; McAllister, Brendan B; Dyck, Richard H; Percival, Christopher J; Kurrasch, Deborah M; Cobb, John

    2015-03-01

    Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum.

  11. Automated cerebellar lobule segmentation with application to cerebellar structural analysis in cerebellar disease.

    Science.gov (United States)

    Yang, Zhen; Ye, Chuyang; Bogovic, John A; Carass, Aaron; Jedynak, Bruno M; Ying, Sarah H; Prince, Jerry L

    2016-02-15

    The cerebellum plays an important role in both motor control and cognitive function. Cerebellar function is topographically organized and diseases that affect specific parts of the cerebellum are associated with specific patterns of symptoms. Accordingly, delineation and quantification of cerebellar sub-regions from magnetic resonance images are important in the study of cerebellar atrophy and associated functional losses. This paper describes an automated cerebellar lobule segmentation method based on a graph cut segmentation framework. Results from multi-atlas labeling and tissue classification contribute to the region terms in the graph cut energy function and boundary classification contributes to the boundary term in the energy function. A cerebellar parcellation is achieved by minimizing the energy function using the α-expansion technique. The proposed method was evaluated using a leave-one-out cross-validation on 15 subjects including both healthy controls and patients with cerebellar diseases. Based on reported Dice coefficients, the proposed method outperforms two state-of-the-art methods. The proposed method was then applied to 77 subjects to study the region-specific cerebellar structural differences in three spinocerebellar ataxia (SCA) genetic subtypes. Quantitative analysis of the lobule volumes shows distinct patterns of volume changes associated with different SCA subtypes consistent with known patterns of atrophy in these genetic subtypes. PMID:26408861

  12. Autosomal recessive cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Palau Francesc

    2006-11-01

    Full Text Available Abstract Autosomal recessive cerebellar ataxias (ARCA are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000, ataxia-telangiectasia (1–2.5/100,000 and early onset cerebellar ataxia with retained tendon reflexes (1/100,000. Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder, ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED, aprataxin in ataxia with oculomotor apraxia (AOA1, and senataxin in ataxia with oculomotor apraxia (AOA2. Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning, electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.

  13. The effects of undernutrition on connectivity in the cerebellar cortex of adult rats.

    OpenAIRE

    Yucel, F; Warren, M. A.; Gumusburun, E

    1994-01-01

    The effects of a 30 d period of undernutrition, followed in some animals by nutritional rehabilitation, on neuronal connectivity in adult rat cerebellum were investigated using the disector method. There was no significant difference between well fed (719 +/- 74, mean +/- S.E.) and undernourished (709 +/- 53) synapse-to-neuron ratios in 134-d-old rat cerebellar cortex, nor was there a significant difference in synapse-to-neuron ratios between control animals (941 +/- 71) and previously undern...

  14. Cerebellar Malformations and Cognitive Disdorders

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-10-01

    Full Text Available The behavioral developmental profile of 27 children and adults (17 males and 10 females with congenital cerebellar malformations was determined in a clinical, neuroradiological and neuropsychological study at the Scientific Institute 'E Medea', University of Milano, Italy.

  15. Complex partial seizures: cerebellar metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Theodore, W.H.; Fishbein, D.; Deitz, M.; Baldwin, P.

    1987-07-01

    We used positron emission tomography (PET) with (/sup 18/F)2-deoxyglucose to study cerebellar glucose metabolism (LCMRglu) and the effect of phenytoin (PHT) in 42 patients with complex partial seizures (CPS), and 12 normal controls. Mean +/- SD patient LCMRglu was 6.9 +/- 1.8 mg glucose/100 g/min (left = right), significantly lower than control values of 8.5 +/- 1.8 (left, p less than 0.006), and 8.3 +/- 1.6 (right, p less than 0.02). Only four patients had cerebellar atrophy on CT/MRI; cerebellar LCMRglu in these was 5.5 +/- 1.5 (p = 0.054 vs. total patient sample). Patients with unilateral temporal hypometabolism or EEG foci did not have lateralized cerebellar hypometabolism. Patients receiving phenytoin (PHT) at the time of scan and patients with less than 5 years total PHT exposure had lower LCMRglu, but the differences were not significant. There were weak inverse correlations between PHT level and cerebellar LCMRglu in patients receiving PHT (r = -0.36; 0.05 less than p less than 0.1), as well as between length of illness and LCMRglu (r = -0.22; 0.05 less than p less than 0.1). Patients with complex partial seizures have cerebellar hypometabolism that is bilateral and due only in part to the effect of PHT.

  16. Timing tasks synchronize cerebellar and frontal ramping activity and theta oscillations: Implications for cerebellar stimulation in diseases of impaired cognition

    Directory of Open Access Journals (Sweden)

    Krystal Lynn Parker

    2016-01-01

    Full Text Available Timing is a fundamental and highly conserved mammalian capability yet the underlying neural mechanisms are widely debated. Ramping activity of single neurons that gradually increase or decrease activity to encode the passage of time, has been speculated to predict a behaviorally relevant temporal event. Cue-evoked low-frequency activity has also been implicated in temporal processing. Ramping activity and low-frequency oscillations occur throughout the brain and could indicate a network-based approach to timing. Temporal processing requires cognitive mechanisms of working memory, attention, and reasoning which are dysfunctional in neuropsychiatric disease. Therefore, timing tasks could be used to probe cognition in animals with disease phenotypes. The medial frontal cortex and cerebellum are involved in cognition. Cerebellar stimulation has been shown to influence medial frontal activity and improve cognition in schizophrenia. However, the mechanism underlying the efficacy of cerebellar stimulation is unknown. Here we discuss how timing tasks can be used to probe cerebellar interactions with the frontal cortex and the therapeutic potential of cerebellar stimulation. The goal of this theory and hypothesis manuscript is threefold. First, we will summarize evidence indicating that in addition to motor learning, timing tasks involve cognitive processes that are present within both the cerebellum and medial frontal cortex. Second, we propose methodologies to investigate the connections between these areas in patients with Parkinson’s disease, autism, and schizophrenia. We hypothesis that cerebellar transcranial stimulation may rescue medial frontal ramping activity, theta oscillations, and timing abnormalities, thereby restoring executive function in diseases of impaired cognition. These hypotheses could inspire the use of timing tasks as biomarkers for neuronal and cognitive abnormalities in neuropsychiatric disease and promote the therapeutic

  17. Direct and indirect spino-cerebellar pathways: shared ideas but different functions in motor control

    Directory of Open Access Journals (Sweden)

    Juan eJiang

    2015-07-01

    Full Text Available The impressive precision of mammalian limb movements relies on internal feedback pathways that convey information about ongoing motor output to cerebellar circuits. The spino-cerebellar tracts (SCT in the cervical, thoracic and lumbar spinal cord have long been considered canonical neural substrates for the conveyance of internal feedback signals. Here we consider the distinct features of an indirect spino-cerebellar route, via the brainstem lateral reticular nucleus (LRN, and the implications of this pre-cerebellar ‘detour’ for the execution and evolution of limb motor control. Both direct and indirect spino-cerebellar pathways signal spinal interneuronal activity to the cerebellum during movements, but evidence suggests that direct SCT neurons are mainly modulated by rhythmic activity, whereas the LRN also receives information from systems active during postural adjustment, reaching and grasping. Thus, while direct and indirect spino-cerebellar circuits can both be regarded as internal copy pathways, it seems likely that the direct system is principally dedicated to rhythmic motor acts like locomotion, while the indirect system also provides a means of pre-cerebellar integration relevant to the execution and coordination of de

  18. Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

    Directory of Open Access Journals (Sweden)

    Yubin Wang

    2016-06-01

    Full Text Available A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1, which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

  19. Defects in the CAPN1 gene result in alterations in cerebellar development and in cerebellar ataxia in mice and humans

    Science.gov (United States)

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hamad, Monia Ben; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-01-01

    SUMMARY A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous CAPN1 null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knock-out (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1 mediated cleavage of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis, and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. PMID:27320912

  20. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains

    OpenAIRE

    Babij, Rachel; Lee, Michelle; Cortés, Etty; Vonsattel, Jean-Paul G.; Faust, Phyllis L.; Louis, Elan D.

    2013-01-01

    Growing clinical, neuro-imaging and post-mortem data have implicated the cerebellum as playing an important role in the pathogenesis of essential tremor. Aside from a modest reduction of Purkinje cells in some post-mortem studies, Purkinje cell axonal swellings (torpedoes) are present to a greater degree in essential tremor cases than controls. Yet a detailed study of more subtle morphometric changes in the Purkinje cell axonal compartment has not been undertaken. We performed a detailed morp...

  1. Posturography of ataxia induced by Coriolis- and Purkinje-effects.

    Science.gov (United States)

    Fitger, C; Brandt, T

    1982-02-01

    Vestibular Coriolis- and Purkinje-effect, which are known to induce vertigo, were investigated with respect to body posture. One aim of this investigation was to provide information concerning clinical vertigo symptoms. Standing on a rotatable stabilometer, 25 healthy subjects had to execute lateral head tilts during (Coriolis), or after (Purkinje), rotation varied with different constant velocities. The conditions were varied with respect to eyes open vs. eyes closed, head upright vs. head tilt to the right and left, direction of rotation clockwise vs. counterclockwise, active vs. passive head tilt, and active vs. passive body rotation. The results supported the expectation that destabilization was less severe with open than with closed eyes and that sway amplitudes were increased after head tilt as well as with a higher velocity of rotation. The direction of the induced body shift was, as expected, opposite to the initial vestibular stimulus. A forward shift after stop without head tilt was frequently found, being independent of the previous direction of rotation. Reported perceptions coincided mostly not with the initial vestibular signal but rather with the actual movement of compensation. Active instead of passive movements did not produce clearly different effects. The Purkinje experiment appeared to be equivalent to the situation when a patient with an acute lesion of a horizontal vestibular canal bends his head. The stabilogram under this condition may allow a prediction of the side of the lesion.

  2. Cognition and Emotion in Cerebellar Disorders

    Science.gov (United States)

    ... FREQUENTLY ASKED QUESTIONS ABOUT... Cognition and Emotion in Cerebellar Disorders Are problems in the areas of cognition and ... active investigation. Why is this important for the ataxia patient? Cerebellar patients and families generally find it helpful to ...

  3. Familial cerebellar ataxia and diabetes insipidus.

    OpenAIRE

    Robinson, I C; O'Malley, B P; Young, I D

    1988-01-01

    Two sisters are reported who both developed partial cranial diabetes insipidus in their 4th decade, followed by progressive cerebellar ataxia. This appears to be the first report of cerebellar ataxia and diabetes insipidus occurring together as a genetic entity.

  4. Releasing dentate nucleus cells from Purkinje cell inhibition generates output from the cerebrocerebellum.

    Directory of Open Access Journals (Sweden)

    Takahiro Ishikawa

    Full Text Available The cerebellum generates its vast amount of output to the cerebral cortex through the dentate nucleus (DN that is essential for precise limb movements in primates. Nuclear cells in DN generate burst activity prior to limb movement, and inactivation of DN results in cerebellar ataxia. The question is how DN cells become active under intensive inhibitory drive from Purkinje cells (PCs. There are two excitatory inputs to DN, mossy fiber and climbing fiber collaterals, but neither of them appears to have sufficient strength for generation of burst activity in DN. Therefore, we can assume two possible mechanisms: post-inhibitory rebound excitation and disinhibition. If rebound excitation works, phasic excitation of PCs and a concomitant inhibition of DN cells should precede the excitation of DN cells. On the other hand, if disinhibition plays a primary role, phasic suppression of PCs and activation of DN cells should be observed at the same timing. To examine these two hypotheses, we compared the activity patterns of PCs in the cerebrocerebellum and DN cells during step-tracking wrist movements in three Japanese monkeys. As a result, we found that the majority of wrist-movement-related PCs were suppressed prior to movement onset and the majority of wrist-movement-related DN cells showed concurrent burst activity without prior suppression. In a minority of PCs and DN cells, movement-related increases and decreases in activity, respectively, developed later. These activity patterns suggest that the initial burst activity in DN cells is generated by reduced inhibition from PCs, i.e., by disinhibition. Our results indicate that suppression of PCs, which has been considered secondary to facilitation, plays the primary role in generating outputs from DN. Our findings provide a new perspective on the mechanisms used by PCs to influence limb motor control and on the plastic changes that underlie motor learning in the cerebrocerebellum.

  5. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    Science.gov (United States)

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled. PMID:25417189

  6. An agonist–antagonist cerebellar nuclear system controlling eyelid kinematics during motor learning

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    Raudel eSánchez-Campusano

    2012-03-01

    Full Text Available The presence of two antagonistic groups of deep cerebellar nuclei neurons has been reported as necessary for a proper dynamic control of learned motor responses. Most models of cerebellar function seem to ignore the biomechanical need for a double activation–deactivation system controlling eyelid kinematics, since most of them accept that, for closing the eyelid, only the activation of the orbicularis oculi muscle (via the red nucleus to the facial motor nucleus is necessary, without a simultaneous deactivation of levator palpebrae motoneurons (via unknown pathways projecting to the perioculomotor area. We have analyzed the kinetic neural commands of two antagonistic types of cerebellar posterior interpositus neuron (types A and B, the electromyographic activity of the orbicularis oculi muscle, and eyelid kinematic variables in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. We addressed the hypothesis that the interpositus nucleus can be considered an agonist–antagonist system controlling eyelid kinematics during motor learning. To carry out a comparative study of the kinetic–kinematic relationships, we applied timing and dispersion pattern analyses. We concluded that, in accordance with a dominant role of cerebellar circuits for the facilitation of flexor responses, type A neurons fire during active eyelid downward displacements ─ i.e., during the active contraction of the orbicularis oculi muscle. In contrast, type B neurons present a high tonic rate when the eyelids are wide open, and stop firing during any active downward displacement of the upper eyelid. From a functional point of view, it could be suggested that type B neurons play a facilitative role for the antagonistic action of the levator palpebrae muscle. From an anatomical point of view, the possibility that cerebellar nuclear type B neurons project to the perioculomotor area ─ i.e., more or less directly onto levator palpebrae

  7. Deficiency of the miR-29a/b-1 cluster leads to ataxic features and cerebellar alterations in mice

    DEFF Research Database (Denmark)

    Papadopoulou, Aikaterini S; Serneels, Lutgarde; Achsel, Tilmann;

    2015-01-01

    miR-29 is expressed strongly in the brain and alterations in expression have been linked to several neurological disorders. To further explore the function of this miRNA in the brain, we generated miR-29a/b-1 knockout animals. Knockout mice develop a progressive disorder characterized by locomotor...... impairment and ataxia. The different members of the miR-29 family are strongly expressed in neurons of the olfactory bulb, the hippocampus and in the Purkinje cells of the cerebellum. Morphological analysis showed that Purkinje cells are smaller and display less dendritic arborisation compared...... to their wildtype littermates. In addition, a decreased number of parallel fibers form synapses on the Purkinje cells. We identified several mRNAs significantly up-regulated in the absence of the miR-29a/b-1 cluster. At the protein level, however, the voltage-gated potassium channel Kcnc3 (Kv3.3) was significantly...

  8. Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

    OpenAIRE

    Garcia-Martinez, Eva Maria; Sanz-Blasco, Sara; Karachitos, Andonis; Bandez, Miguel J.; Fernandez-Gomez, Francisco J.; Perez-Alvarez, Sergio; Mera, Raquel Maria Melero Fernandez De; Jordan, Maria J.; Aguirre, Norberto; Galindo, Maria F.; Villalobos, Carlos; Navarro, Ana; Kmita, Hanna; Jordán, Joaquín

    2009-01-01

    Abstract Minocycline, an antibiotic of the tetracycline family, has attracted considerable interest for its theoretical therapeutic applications in neurodegenerative diseases. However, the mechanism of action underlying its effect remains elusive. Here we have studied the effect of minocycline under excitotoxic conditions. Fluorescence and bioluminescence imaging studies in rat cerebellar granular neuron cultures using fura-2/AM and mitochondria-targeted aequorin revealed that mino...

  9. Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex.

    Directory of Open Access Journals (Sweden)

    Weiping Zhang

    Full Text Available Calcium-activated chloride channels of the anoctamin (alias TMEM16 protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum.

  10. Electrophysiological Monitoring of Injury ProgressionIn the Rat Cerebellar Cortex

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    Gokhan eOrdek

    2014-10-01

    Full Text Available The changes of excitability in affected neural networks can be used as a marker to study the temporal course of traumatic brain injury (TBI. The cerebellum is an ideal platform to study brain injury mechanisms at the network level using the electrophysiological methods. Within its crystalline morphology, the cerebellar cortex contains highly organized topographical subunits that are defined by two main inputs, the climbing and mossy fibers. Here we demonstrate the use of cerebellar evoked potentials (EPs mediated through these afferent systems for monitoring the injury progression in a rat model of fluid percussion injury (FPI. A mechanical tap on the dorsal hand was used as a stimulus, and EPs were recorded from the paramedian lobule (PML of the posterior cerebellum via multi-electrode arrays (MEA. Post-injury evoked response amplitudes (EPAs were analyzed on a daily basis for one week and compared with pre-injury values. We found a trend of consistently decreasing EPAs in all nine animals, losing as much as 72±4% of baseline amplitudes measured before the injury. Notably, our results highlighted two particular time windows; the first 24 hours of injury in the acute period and day-3 to day-7 in the delayed period where the largest drops (~50% and 24% were observed in the EPAs. In addition, cross-correlations of spontaneous signals between electrode pairs declined (from 0.47±0.1 to 0.35±0.04, p<0.001 along with the EPAs throughout the week of injury. In support of the electrophysiological findings, immunohistochemical analysis at day-7 post-injury showed detectable Purkinje cell loss at low FPI pressures and more with the largest pressures used. Our results suggest that sensory evoked potentials recorded from the cerebellar surface can be a useful technique to monitor the course of cerebellar injury and identify the phases of injury progression even at mild levels.

  11. Language Impairment in Cerebellar Ataxia

    NARCIS (Netherlands)

    van Gaalen, Judith; de Swart, Bert J. M.; Oostveen, Judith; Knuijt, Simone; van de Warrenburg, Bart P. C.; Kremer, Berry (H. ) P. H.

    2014-01-01

    Background: Several studies have suggested that language impairment can be observed in patients with cerebellar pathology. The aim of this study was to investigate language performance in patients with spinocerebellar ataxia type 6 (SCA6). Methods: We assessed speech and language in 29 SCA6 patients

  12. Speech Prosody in Cerebellar Ataxia

    Science.gov (United States)

    Casper, Maureen A.; Raphael, Lawrence J.; Harris, Katherine S.; Geibel, Jennifer M.

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy…

  13. Cerebellar fMRI Activation Increases with Increasing Working Memory Demands.

    Science.gov (United States)

    Küper, M; Kaschani, P; Thürling, M; Stefanescu, M R; Burciu, R G; Göricke, S; Maderwald, S; Ladd, M E; Hautzel, H; Timmann, D

    2016-06-01

    The aim of the present study was to explore cerebellar contributions to the central executive in n-back working memory tasks using 7-T functional magnetic imaging (fMRI). We hypothesized that cerebellar activation increased with increasing working memory demands. Activations of the cerebellar cortex and dentate nuclei were compared between 0-back (serving as a motor control task), 1-back, and 2-back working memory tasks for both verbal and abstract modalities. A block design was used. Data of 27 participants (mean age 26.6 ± 3.8 years, female/male 12:15) were included in group statistical analysis. We observed that cerebellar cortical activations increased with higher central executive demands in n-back tasks independent of task modality. As confirmed by subtraction analyses, additional bilateral activations following higher executive demands were found primarily in four distinct cerebellar areas: (i) the border region of lobule VI and crus I, (ii) inferior parts of the lateral cerebellum (lobules crus II, VIIb, VIII, IX), (iii) posterior parts of the paravermal cerebellar cortex (lobules VI, crus I, crus II), and (iv) the inferior vermis (lobules VI, VIIb, VIII, IX). Dentate activations were observed for both verbal and abstract modalities. Task-related increases were less robust and detected for the verbal n-back tasks only. These results provide further evidence that the cerebellum participates in an amodal bilateral neuronal network representing the central executive during working memory n-back tasks. PMID:26202670

  14. Quantitative neuroanatomy of all Purkinje cells with light sheet microscopy and high-throughput image analysis.

    Science.gov (United States)

    Silvestri, Ludovico; Paciscopi, Marco; Soda, Paolo; Biamonte, Filippo; Iannello, Giulio; Frasconi, Paolo; Pavone, Francesco S

    2015-01-01

    Characterizing the cytoarchitecture of mammalian central nervous system on a brain-wide scale is becoming a compelling need in neuroscience. For example, realistic modeling of brain activity requires the definition of quantitative features of large neuronal populations in the whole brain. Quantitative anatomical maps will also be crucial to classify the cytoarchtitectonic abnormalities associated with neuronal pathologies in a high reproducible and reliable manner. In this paper, we apply recent advances in optical microscopy and image analysis to characterize the spatial distribution of Purkinje cells (PCs) across the whole cerebellum. Light sheet microscopy was used to image with micron-scale resolution a fixed and cleared cerebellum of an L7-GFP transgenic mouse, in which all PCs are fluorescently labeled. A fast and scalable algorithm for fully automated cell identification was applied on the image to extract the position of all the fluorescent PCs. This vectorized representation of the cell population allows a thorough characterization of the complex three-dimensional distribution of the neurons, highlighting the presence of gaps inside the lamellar organization of PCs, whose density is believed to play a significant role in autism spectrum disorders. Furthermore, clustering analysis of the localized somata permits dividing the whole cerebellum in groups of PCs with high spatial correlation, suggesting new possibilities of anatomical partition. The quantitative approach presented here can be extended to study the distribution of different types of cell in many brain regions and across the whole encephalon, providing a robust base for building realistic computational models of the brain, and for unbiased morphological tissue screening in presence of pathologies and/or drug treatments. PMID:26074783

  15. Global dysrhythmia of cerebro-basal ganglia-cerebellar networks underlies motor tics following striatal disinhibition.

    Science.gov (United States)

    McCairn, Kevin W; Iriki, Atsushi; Isoda, Masaki

    2013-01-01

    Motor tics, a cardinal symptom of Tourette syndrome (TS), are hypothesized to arise from abnormalities within cerebro-basal ganglia circuits. Yet noninvasive neuroimaging of TS has previously identified robust activation in the cerebellum. To date, electrophysiological properties of cerebellar activation and its role in basal ganglia-mediated tic expression remain unknown. We performed multisite, multielectrode recordings of single-unit activity and local field potentials from the cerebellum, basal ganglia, and primary motor cortex using a pharmacologic monkey model of motor tics/TS. Following microinjections of bicuculline into the sensorimotor putamen, periodic tics occurred predominantly in the orofacial region, and a sizable number of cerebellar neurons showed phasic changes in activity associated with tic episodes. Specifically, 64% of the recorded cerebellar cortex neurons exhibited increases in activity, and 85% of the dentate nucleus neurons displayed excitatory, inhibitory, or multiphasic responses. Critically, abnormal discharges of cerebellar cortex neurons and excitatory-type dentate neurons mostly preceded behavioral tic onset, indicating their central origins. Latencies of pathological activity in the cerebellum and primary motor cortex substantially overlapped, suggesting that aberrant signals may be traveling along divergent pathways to these structures from the basal ganglia. Furthermore, the occurrence of tic movement was most closely associated with local field potential spikes in the cerebellum and primary motor cortex, implying that these structures may function as a gate to release overt tic movements. These findings indicate that tic-generating networks in basal ganglia mediated tic disorders extend beyond classical cerebro-basal ganglia circuits, leading to global network dysrhythmia including cerebellar circuits.

  16. Characterization of NCAM diversity in cultured neurons

    DEFF Research Database (Denmark)

    Gegelashvili, George; Andersson, A M; Schousboe, Arne;

    1993-01-01

    A single transcript of the NCAM gene undergoes differential processing resulting in a multiplicity of mRNAs and their translation products. In this study, the diversity of NCAM in rat primary neuronal cultures was investigated utilizing immuno- and Northern blot analyses. NCAM polypeptides of 190 k......Da (NCAM-A) and 135 kDa (NCAM-B) were shown to be associated with the neuronal phenotype. These data were confirmed by Northern blotting, which in both neocortical neurons and cerebellar granule neurons revealed mRNA classes of 7.4 kb and 6.7 kb encoding for NCAM-A and -B, respectively. However......, oligonucleotide probes, specific for selected exons or exon combinations, revealed special features of cerebellar granule neurons as compared to neocortical neurons: expression of 4.3 kb NCAM mRNA, a relatively low amount of VASE-containing variants, and an apparent lack of mRNA species containing exons alpha...

  17. Sustained Reduction of Cerebellar Activity in Experimental Epilepsy

    Directory of Open Access Journals (Sweden)

    Kim Rijkers

    2015-01-01

    Full Text Available Clinical and experimental evidence suggests a role for the cerebellum in seizure control, while no data are available on cerebellar activity between seizures. We hypothesized that interictal regional activity of the deep cerebellar nuclei is reduced in epilepsy and tested this in an animal model by using ΔFosB and cytochrome oxidase (COX (immunohistochemistry. The expression of these two markers of neuronal activity was analysed in the dentate nucleus (DN, interpositus nucleus (IN, and fastigial nucleus (FN of the cerebellum of fully amygdala kindled rats that were sacrificed 48 hours after their last seizure. The DN and FN of kindled rats exhibited 25 to 29% less ΔFosB immunopositive cells than their respective counterpart in sham controls (P<0.05. COX expression in the DN and FN of kindled animals was reduced by 32 to 33% compared to respective control values (P<0.05. These results indicate that an epileptogenic state is characterized by decreased activity of deep cerebellar nuclei, especially the DN and FN. Possible consequences may include a decreased activation of the thalamus, contributing to further seizure spread. Restoration of FN activity by low frequency electrical stimulation is suggested as a possible treatment option in chronic epilepsy.

  18. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

    DEFF Research Database (Denmark)

    Winkelmann, Juliane; Lin, Ling; Schormair, Barbara;

    2012-01-01

    Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT.......GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding...

  19. Cerebellar ataxia and functional genomics : Identifying the routes to cerebellar neurodegeneration

    NARCIS (Netherlands)

    Smeets, C J L M; Verbeek, D S

    2014-01-01

    Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as Fried

  20. Neuron-Specific Nuclear Antigen NeuN Is Not Detectable In Gerbil Subtantia Nigra Pars Reticulata

    OpenAIRE

    Kumar, Sanjay S.; Buckmaster, Paul S.

    2007-01-01

    NeuN (Neuronal Nuclei), the neuron-specific marker of nuclear protein is used extensively in histological procedures to identify major cell-types in adult vertebrate nervous systems of a variety of species including rodents and humans. Some notable exceptions (i.e., NeuN-negative neurons) include Purkinje cells in cerebellum, mitral cells in olfactory bulb, and photoreceptors in retina. Here we report that neurons in gerbil (Meriones unguiculatus) substantia nigra pars reticulata (SNr), whose...

  1. Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation

    Directory of Open Access Journals (Sweden)

    Forman Oliver P

    2012-07-01

    Full Text Available Abstract Background Neonatal cerebellar cortical degeneration is a neurodegenerative disease described in several canine breeds including the Beagle. Affected Beagles are unable to ambulate normally from the onset of walking and the main pathological findings include Purkinje cell loss with swollen dendritic processes. Previous reports suggest an autosomal recessive mode of inheritance. The development of massively parallel sequencing techniques has presented the opportunity to investigate individual clinical cases using genome-wide sequencing approaches. We used genome-wide mRNA sequencing (mRNA-seq of cerebellum tissue from a single Beagle with neonatal cerebellar cortical degeneration as a method of candidate gene sequencing, with the aim of identifying the causal mutation. Results A four-week old Beagle dog presented with progressive signs of cerebellar ataxia and the owner elected euthanasia. Histopathology revealed findings consistent with cerebellar cortical degeneration. Genome-wide mRNA sequencing (mRNA-seq of RNA from cerebellum tissue was used as a method of candidate gene sequencing. After analysis of the canine orthologues of human spinocerebellar ataxia associated genes, we identified a homozygous 8 bp deletion in the β-III spectrin gene, SPTBN2, associated with spinocerebellar type 5 in humans. Genotype analysis of the sire, dam, ten clinically unaffected siblings, and an affected sibling from a previous litter, showed the mutation to fully segregate with the disorder. Previous studies have shown that β-III spectrin is critical for Purkinje cell development, and the absence of this protein can lead to cell damage through excitotoxicity, consistent with the observed Purkinje cell loss, degeneration of dendritic processes and associated neurological dysfunction in this Beagle. Conclusions An 8 bp deletion in the SPTBN2 gene encoding β-III spectrin is associated with neonatal cerebellar cortical degeneration in Beagle dogs

  2. Cerebellar medulloblastoma presenting with skeletal metastasis

    OpenAIRE

    Barai Sukanta; Bandopadhayaya G; Julka P; Dhanapathi H; Haloi A; Seith A

    2004-01-01

    Medulloblastomas are highly malignant brain tumours, but only rarely produce skeletal metastases. No case of medulloblastoma has been documented to have produced skeletal metastases prior to craniotomy or shunt surgery. A 21-year-old male presented with pain in the hip and lower back with difficulty in walking of 3 months′ duration. Signs of cerebellar dysfunction were present hence a diagnosis of cerebellar neoplasm or skeletal tuberculosis with cerebellar abscess formation was consid...

  3. Crossed cerebral - cerebellar diaschisis : MRI evaluation.

    Directory of Open Access Journals (Sweden)

    Chakravarty A

    2002-07-01

    Full Text Available MRI, done later in life, in two patients with infantile hemiplegia syndrome showed significant volume loss in the cerebellar hemisphere contralateral to the side of the affected cerebrum. The cerebellar volume loss seemed to correlate with the degree of volume loss in the contralateral cerebral hemisphere. These observations provide morphological evidence of the phenomenon of crossed cerebral-cerebellar diaschisis (CCD. Functional neuroimaging studies in support of the concept of CCD has been critically reviewed.

  4. Autosomal recessive cerebellar ataxias : the current state of affairs

    NARCIS (Netherlands)

    Vermeer, S.; van de Warrenburg, B. P. C.; Willemsen, M. A. A. P.; Cluitmans, M.; Scheffer, H.; Kremer, B. P.; Knoers, N. V. A. M.

    2011-01-01

    Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, an

  5. Spike-coding mechanisms of cerebellar temporal processing in classical conditioning and voluntary movements.

    Science.gov (United States)

    Yamaguchi, Kenji; Sakurai, Yoshio

    2014-10-01

    Time is a fundamental and critical factor in daily life. Millisecond timing, which is the underlying temporal processing for speaking, dancing, and other activities, is reported to rely on the cerebellum. In this review, we discuss the cerebellar spike-coding mechanisms for temporal processing. Although the contribution of the cerebellum to both classical conditioning and voluntary movements is well known, the difference of the mechanisms for temporal processing between classical conditioning and voluntary movements is not clear. Therefore, we review the evidence of cerebellar temporal processing in studies of classical conditioning and voluntary movements and report the similarities and differences between them. From some studies, which used tasks that can change some of the temporal properties (e.g., the duration of interstimulus intervals) with keeping identical movements, we concluded that classical conditioning and voluntary movements may share a common spike-coding mechanism because simple spikes in Purkinje cells decrease at predicted times for responses regardless of the intervals between responses or stimulation.

  6. Deiters' Nucleus. Its Role in Cerebellar Ideogenesis : The Ferdinando Rossi Memorial Lecture.

    Science.gov (United States)

    Voogd, Jan

    2016-02-01

    Otto Deiters (1834-1863) was a promising neuroscientist who, like Ferdinando Rossi, died too young. His notes and drawings were posthumously published by Max Schultze in the book "Untersuchungen über Gehirn und Rückenmark." The book is well-known for his dissections of nerve cells, showing the presence of multiple dendrites and a single axon. Deiters also made beautiful drawings of microscopical sections through the spinal cord and the brain stem, the latter showing the lateral vestibular nucleus which received his name. This nucleus, however, should be considered as a cerebellar nucleus because it receives Purkinje cell axons from the vermal B zone in its dorsal portion. Afferents from the labyrinth occur in its ventral part. The nucleus gives rise to the lateral vestibulospinal tract. The cerebellar B module of which Deiters' nucleus is the target nucleus was used in many innovative studies of the cerebellum on the zonal organization of the olivocerebellar projection, its somatotopical organization, its microzones, and its role in posture and movement that are the subject of this review.

  7. Circadian oscillations of molecular clock components in the cerebellar cortex of the rat.

    Science.gov (United States)

    Rath, Martin F; Rohde, Kristian; Møller, Morten

    2012-12-01

    The central circadian clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the circadian clockwork of the SCN constitutes a self-sustained autoregulatory feedback mechanism reflected by the rhythmic expression of clock genes. However, recent studies have shown the presence of extrahypothalamic oscillators in other areas of the brain including the cerebellum. In the present study, the authors unravel the cerebellar molecular clock by analyzing clock gene expression in the cerebellum of the rat by use of radiochemical in situ hybridization and quantitative real-time polymerase chain reaction. The authors here show that all core clock genes, i.e., Per1, Per2, Per3, Cry1, Cry2, Clock, Arntl, and Nr1d1, as well as the clock-controlled gene Dbp, are expressed in the granular and Purkinje cell layers of the cerebellar cortex. Among these genes, Per1, Per2, Per3, Cry1, Arntl, Nr1d1, and Dbp were found to exhibit circadian rhythms in a sequential temporal manner similar to that of the SCN, but with several hours of delay. The results of lesion studies indicate that the molecular oscillatory profiles of Per1, Per2, and Cry1 in the cerebellum are controlled, though possibly indirectly, by the central clock of the SCN. These data support the presence of a circadian oscillator in the cortex of the rat cerebellum.

  8. Crossed cerebellar hyperperfusion in brain perfusion SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Jinnouchi, Seishi; Nagamachi, Shigeki; Nishii, Ryuuichi; Futami, Shigemi; Tamura, Shozo [Miyazaki Medical Coll., Kiyotake (Japan); Kawai, Keiichi

    2000-10-01

    Crossed cerebellar diaschisis is a well-known brain SPECT finding in stroke patients. Few reports, however, have described supratentorial and contralateral cerebellar hyperperfusion (crossed cerebellar hyperperfusion, CCH). We assessed the incidence of CCH in 33 patients with cerebral hyperperfusion. Brain SPECT showed CCH in five patients out of 20 epilepsy and three of 13 patients with acute encephalitis. These eight patients with CCH had recent epileptic attack. CCH was found in ECD SPECT as well as HM-PAO. The contralateral cerebellar activity correlated with the cerebral activity in patients with CCH. CCH would have a relation with supratentrial hyperfunction in epilepsy and acute encephalitis. (author)

  9. [Peripheral neuropathies associated with hereditary cerebellar ataxias].

    Science.gov (United States)

    Anheim, M; Tranchant, C

    2011-01-01

    Inherited cerebellar ataxias constitute a complicated and heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or spinocerebellar tract, spinal cord and peripheral nerves. A peripheral neuropathy is frequently seen in inherited cerebellar ataxias although it rarely reveals the disease. Moreover, the peripheral neuropathy is helpful for the diagnostic procedure and contributes to the functional prognosis of the disease. Thus, electroneuromyography is essential in the algorithm for the diagnosis of inherited cerebellar ataxias, as well as brain MRI (looking especially for cerebellar atrophy) and the assessment of several biomarkers (alpha-foetoprotein, vitamin E, albumin, LDL cholesterol, lactic acid, phytanic acid).

  10. Cerebellar-dependent associative learning is preserved in Duchenne muscular dystrophy: a study using delay eyeblink conditioning.

    Directory of Open Access Journals (Sweden)

    Ulrike Schara

    Full Text Available Besides progressive muscle weakness cognitive deficits have been reported in patients with Duchenne muscular dystrophy (DMD. Cerebellar dysfunction has been proposed to explain cognitive deficits at least in part. In animal models of DMD disturbed Purkinje cell function has been shown following loss of dystrophin. Furthermore there is increasing evidence that the lateral cerebellum contributes to cognitive processing. In the present study cerebellar-dependent delay eyeblink conditioning, a form of associative learning, was used to assess cerebellar function in DMD children.Delay eyeblink conditioning was examined in eight genetically defined male patients with DMD and in ten age-matched control subjects. Acquisition, timing and extinction of conditioned eyeblink responses (CR were assessed during a single conditioning session.Both groups showed a significant increase of CRs during the course of learning (block effect p < 0.001. CR acquisition was not impaired in DMD patients (mean total CR incidence 37.4 ± 17.6% as compared to control subjects (36.2 ± 17.3%; group effect p = 0.89; group by block effect p = 0.38; ANOVA with repeated measures. In addition, CR timing and extinction was not different from controls.Delay eyeblink conditioning was preserved in the present DMD patients. Because eyeblink conditioning depends on the integrity of the intermediate cerebellum, this older part of the cerebellum may be relatively preserved in DMD. The present findings agree with animal model data showing that the newer, lateral cerebellum is primarily affected in DMD.

  11. 2', 3'-cyclic nucleotide 3'-phosphodiesterase is expressed in dissociated rat cerebellar cells and included in the postsynaptic density fraction.

    Science.gov (United States)

    Cho, Sun-Jung; Jung, Jae Seob; Jin, IngNyol; Moon, Il Soo

    2003-08-31

    We have shown by protein sequencing that the phosphotyrosine-containing 48 kDa protein band of the rat cerebellar postsynaptic density fraction (CBL-PSD) is 2', 3'-cyclic nucleotide 3'-phosphodiesterase 2 (CNP2). Immunoblot analysis indicated that both CNP1 and CNP2 isoforms are present in the CBL-PSD fraction, whereas there is little CNP2 in the forebrain (FB)-PSD fraction. Both isoforms in the CBL-PSD fraction were tyrosine-phosphorylated to a basal extent. They were efficiently dissociated from the complexes in the PSD fraction by salt, but not by non-ionic detergents such as n-octyl glucoside (OG) and Triton X-100. Immunocytochemistry of dissociated cerebellar cultures revealed patchy CNP staining in oligodendrocytes (OLs), Purkinje cells (PCs), and unidentified PSD95-positive cells, but no staining in granule cells (GCs). Our results indicate that both CNP1 and CNP2 are expressed in cerian populations of cerebellar cells in addition to OL, and that they are associated with complexes that are co-isolated with the PSD. PMID:14503857

  12. Fetal MRI and antenatal diagnosis of unilateral cerebellar hypoplasia

    OpenAIRE

    Houda El Mhabrech; Ahmed Zrig; Chiraz Hafsa

    2015-01-01

    Focal cerebellar hypoplasia is restricted to one cerebellar hemisphere or to the vermis. Prenatal diagnosis of unilateral cerebellar hypoplasia is possible by the use of ultrasound and MRI. Familiarity with the prenatal MRI findings is essential to recognize cerebellar pathologies accurately and prospectively. We present US and MRI findings in a fetus with cerebellar malformation at 20 weeks gestation. The goal of our case report is to present the fetal MRI findings of unilateral cerebellar h...

  13. Virtual NEURON: a strategy for merged biochemical and electrophysiological modeling.

    Science.gov (United States)

    Brown, Sherry-Ann; Moraru, Ion I; Schaff, James C; Loew, Leslie M

    2011-10-01

    Because of its highly branched dendrite, the Purkinje neuron requires significant computational resources if coupled electrical and biochemical activity are to be simulated. To address this challenge, we developed a scheme for reducing the geometric complexity; while preserving the essential features of activity in both the soma and a remote dendritic spine. We merged our previously published biochemical model of calcium dynamics and lipid signaling in the Purkinje neuron, developed in the Virtual Cell modeling and simulation environment, with an electrophysiological model based on a Purkinje neuron model available in NEURON. A novel reduction method was applied to the Purkinje neuron geometry to obtain a model with fewer compartments that is tractable in Virtual Cell. Most of the dendritic tree was subject to reduction, but we retained the neuron's explicit electrical and geometric features along a specified path from spine to soma. Further, unlike previous simplification methods, the dendrites that branch off along the preserved explicit path are retained as reduced branches. We conserved axial resistivity and adjusted passive properties and active channel conductances for the reduction in surface area, and cytosolic calcium for the reduction in volume. Rallpacks are used to validate the reduction algorithm and show that it can be generalized to other complex neuronal geometries. For the Purkinje cell, we found that current injections at the soma were able to produce similar trains of action potentials and membrane potential propagation in the full and reduced models in NEURON; the reduced model produces identical spiking patterns in NEURON and Virtual Cell. Importantly, our reduced model can simulate communication between the soma and a distal spine; an alpha function applied at the spine to represent synaptic stimulation gave similar results in the full and reduced models for potential changes associated with both the spine and the soma. Finally, we combined

  14. Rabbit cerebellar slice analysis of long-term depression and its role in classical conditioning.

    Science.gov (United States)

    Schreurs, B G; Alkon, D L

    1993-12-24

    Cerebellar long-term depression (LTD) has been proposed as a mechanism underlying classical conditioning of the rabbit nictitating membrane/eyelid response (NMR). However, LTD has only been obtained reliably when (1) cerebellar slices are bathed in GABA antagonists which abolish disynaptic inhibitory post synaptic potentials, and (2) the temporal sequence of stimulation used in slice or intact preparations is the opposite of that used in classical conditioning. Based on intradendritic Purkinje cell recordings obtained from rabbit cerebellar slices, we report that stimulation of climbing fibers and then parallel fibers in the presence of the GABA antagonist, bicuculline, produced significant depression of parallel fiber excitatory post synaptic potential (epsp) amplitude that continued to increase for at least 20 min after stimulation. However, application of the same stimulation protocol without GABA antagonists produced a brief depression of parallel fiber epsps that disappeared within minutes. Activation of parallel fibers and then climbing fibers in an order opposite to the LTD-producing sequence (i.e. a classical conditioning-like order) produced a brief depression that dissipated quickly. Stimulation of parallel fibers alone produced a small, slowly developing potentiation, but stimulation of parallel fibers during depolarization-induced local dendritic calcium spikes produced significant depression almost immediately which then declined slowly to more modest levels. Finally, stimulation of parallel fibers at frequencies used in in vivo parallel fiber-climbing fiber stimulation experiments (e.g. 100 Hz) produced an immediate and profound long-lasting epsp depression. The depression occurred, however, whether parallel and climbing fibers were stimulated separately (unpaired) or in a classical conditioning-like protocol (paired) where parallel fiber stimulation coterminated with climbing fiber stimulation (10 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)

  15. The clinical presentation of preterm cerebellar haemorrhage

    NARCIS (Netherlands)

    G.M. Ecury-Goossen (Ginette); J. Dudink (Jeroen); M. Leguin (Maarten); M. Feijen-Roon (Monique); S. Horsch (Sandra); P. Govaert (Paul)

    2010-01-01

    textabstractThe objective of this study was to evaluate clinical symptoms and findings on cranial ultrasound (CUS) in preterm infants with cerebellar haemorrhage through retrospective analysis of all preterm infants with a postnatal CUS or MRI diagnosis of cerebellar haemorrhage admitted in a tertia

  16. Altered cerebellar feedback projections in Asperger syndrome.

    Science.gov (United States)

    Catani, Marco; Jones, Derek K; Daly, Eileen; Embiricos, Nitzia; Deeley, Quinton; Pugliese, Luca; Curran, Sarah; Robertson, Dene; Murphy, Declan G M

    2008-07-15

    It has been proposed that the biological basis of autism spectrum disorder includes cerebellar 'disconnection'. However, direct in vivo evidence in support of this is lacking. Here, the microstructural integrity of cerebellar white matter in adults with Asperger syndrome was studied using diffusion tensor magnetic resonance tractography. Fifteen adults with Asperger syndrome and 16 age-IQ-gender-matched healthy controls underwent diffusion tensor magnetic resonance imaging. For each subject, tract-specific measurements of mean diffusivity and fractional anisotropy were made within the inferior, middle, superior cerebellar peduncles and short intracerebellar fibres. No group differences were observed in mean diffusivity. However, people with Asperger syndrome had significantly lower fractional anisotropy in the short intracerebellar fibres (pAsperger syndrome. The localised abnormalities in the main cerebellar outflow pathway may prevent the cerebral cortex from receiving those cerebellar feedback inputs necessary for a successful adaptive social behaviour.

  17. Cerebellar stroke-manifesting as mania

    Directory of Open Access Journals (Sweden)

    Venkatesan Jagadesan

    2014-01-01

    Full Text Available Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed.

  18. Cerebellar Ataxia and Glutamic Acid Decarboxylase Antibodies

    Science.gov (United States)

    Ariño, Helena; Gresa-Arribas, Nuria; Blanco, Yolanda; Martínez-Hernández, Eugenia; Sabater, Lidia; Petit-Pedrol, Mar; Rouco, Idoia; Bataller, Luis; Dalmau, Josep O.; Saiz, Albert; Graus, Francesc

    2016-01-01

    IMPORTANCE Current clinical and immunologic knowledge on cerebellar ataxia (CA) with glutamic acid decarboxylase 65 antibodies (GAD65-Abs) is based on case reports and small series with short-term follow-up data. OBJECTIVE To report the symptoms, additional antibodies, prognostic factors, and long-term outcomes in a cohort of patients with CA and GAD65-Abs. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study and laboratory investigations at a center for autoimmune neurologic disorders among 34 patients with CA and GAD65-Abs, including 25 with long-term follow-up data (median, 5.4 years; interquartile range, 3.1-10.3 years). MAIN OUTCOMES AND MEASURES Analysis of clinicoimmunologic features and predictors of response to immunotherapy. Immunochemistry on rat brain, cultured neurons, and human embryonic kidney cells expressing GAD65, GAD67, α1-subunit of the glycine receptor, and a repertoire of known cell surface autoantigens were used to identify additional antibodies. Twenty-eight patients with stiff person syndrome and GAD65-Abs served as controls. RESULTS The median age of patients was 58 years (range, 33-80 years); 28 of 34 patients (82%) were women. Nine patients (26%) reported episodes of brainstem and cerebellar dysfunction or persistent vertigo several months before developing CA. The clinical presentation was subacute during a period of weeks in 13 patients (38%). Nine patients (26%) had coexisting stiff person syndrome symptoms. Systemic organ-specific autoimmunities (type 1 diabetes mellitus and others) were present in 29 patients (85%). Twenty of 25 patients with long-term follow-up data received immunotherapy (intravenous immunoglobulin in 10 and corticosteroids and intravenous immunoglobulin or other immunosuppressors in 10), and 7 of them (35%) improved. Predictors of clinical response included subacute onset of CA (odds ratio [OR], 0.50; 95% CI, 0.25-0.99; P = .047) and prompt immunotherapy (OR, 0.98; 95% CI, 0.96-0.99; P = .01). Similar

  19. Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue

    Science.gov (United States)

    D’Angelo, Egidio; Antonietti, Alberto; Casali, Stefano; Casellato, Claudia; Garrido, Jesus A.; Luque, Niceto Rafael; Mapelli, Lisa; Masoli, Stefano; Pedrocchi, Alessandra; Prestori, Francesca; Rizza, Martina Francesca; Ros, Eduardo

    2016-01-01

    The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate “realistic” models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems. PMID:27458345

  20. Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue.

    Science.gov (United States)

    D'Angelo, Egidio; Antonietti, Alberto; Casali, Stefano; Casellato, Claudia; Garrido, Jesus A; Luque, Niceto Rafael; Mapelli, Lisa; Masoli, Stefano; Pedrocchi, Alessandra; Prestori, Francesca; Rizza, Martina Francesca; Ros, Eduardo

    2016-01-01

    The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate "realistic" models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems. PMID:27458345

  1. Cultured neurons as model systems for biochemical and pharmacological studies on receptors for neurotransmitter amino acids

    DEFF Research Database (Denmark)

    Schousboe, A; Drejer, J; Hansen, Gert Helge;

    1985-01-01

    By the use of primary cultures of neurons consisting of cerebral cortex interneurons or cerebellar granule cells it is possible to study biochemical and pharmacological aspects of receptors for GABA and glutamate. Cerebellar granule cells have been shown to express both high- and low-affinity GAB...

  2. The role of Purkinje-myocardial coupling during ventricular arrhythmia: a modeling study.

    Directory of Open Access Journals (Sweden)

    Elham Behradfar

    Full Text Available The Purkinje system is the fast conduction network of the heart which couples to the myocardium at discrete sites called Purkinje-Myocyte Junctions (PMJs. However, the distribution and number of PMJs remains elusive, as does whether a particular PMJ is functional. We hypothesized that the Purkinje system plays a role during reentry and that the number of functional PMJs affect reentry dynamics. We used a computer finite element model of rabbit ventricles in which we varied the number of PMJs. Sustained, complex reentry was induced by applying an electric shock and the role of the Purkinje system in maintaining the arrhythmia was assessed by analyzing phase singularities, frequency of activation, and bidirectional propagation at PMJs. For larger junctional resistances, increasing PMJ density increased the mean firing rate in the Purkinje system, the percentage of successful retrograde conduction at PMJs, and the incidence of wave break on the epicardium. However, the mean firing of the ventricles was not affected. Furthermore, increasing PMJ density above 13/[Formula: see text] did not alter reentry dynamics. For lower junctional resistances, the trend was not as clear. We conclude that Purkinje system topology affects reentry dynamics and conditions which alter PMJ density can alter reentry dynamics.

  3. An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons

    DEFF Research Database (Denmark)

    Neiiendam, Johanne Louise; Køhler, Lene Boding; Christensen, Claus;

    2004-01-01

    interaction with FGFR in primary cultures of three different neuronal cell types all expressing FGFR subtype 1: dopaminergic, hippocampal and cerebellar granule neurons. Moreover, we show that the FGL peptide promotes neuronal survival upon induction of cell death in the same three cell types. The effects...

  4. Stimulation of the N-methyl-D-aspartate receptor has a trophic effect on differentiating cerebellar granule cells

    DEFF Research Database (Denmark)

    Balázs, R; Hack, N; Jørgensen, Ole Steen

    1988-01-01

    N-methyl-D-aspartate (NMDA) supplementation of cerebellar cultures enriched in granule neurones (about 90%) prevented the extensive cell loss which occurs when cultivation takes place, in serum containing media, in the presence of 'low' K+ (5-15 mM). Estimation of tetanus toxin receptors and N...

  5. Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo.

    Science.gov (United States)

    Mitchell, Diana E; Della Santina, Charles C; Cullen, Kathleen E

    2016-01-01

    Although cerebellar mechanisms are vital to maintain accuracy during complex movements and to calibrate simple reflexes, recent in vitro studies have called into question the widely held view that synaptic changes within cerebellar pathways exclusively guide alterations in motor performance. Here we investigate the vestibulo-ocular reflex (VOR) circuitry by applying temporally precise activation of vestibular afferents in awake-behaving monkeys to link plasticity at different neural sites with changes in motor performance. Behaviourally relevant activation patterns produce rapid attenuation of direct pathway VOR neurons, but not their nerve input. Changes in the strength of this pathway are sufficient to induce a lasting decrease in the evoked VOR. In addition, indirect brainstem pathways display complementary nearly instantaneous changes, contributing to compensating for the reduced sensitivity of primary VOR neurons. Taken together, our data provide evidence that multiple sites of plasticity within VOR pathways can rapidly shape motor performance in vivo. PMID:27157829

  6. Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo

    Science.gov (United States)

    Mitchell, Diana E.; Della Santina, Charles C.; Cullen, Kathleen E.

    2016-01-01

    Although cerebellar mechanisms are vital to maintain accuracy during complex movements and to calibrate simple reflexes, recent in vitro studies have called into question the widely held view that synaptic changes within cerebellar pathways exclusively guide alterations in motor performance. Here we investigate the vestibulo-ocular reflex (VOR) circuitry by applying temporally precise activation of vestibular afferents in awake-behaving monkeys to link plasticity at different neural sites with changes in motor performance. Behaviourally relevant activation patterns produce rapid attenuation of direct pathway VOR neurons, but not their nerve input. Changes in the strength of this pathway are sufficient to induce a lasting decrease in the evoked VOR. In addition, indirect brainstem pathways display complementary nearly instantaneous changes, contributing to compensating for the reduced sensitivity of primary VOR neurons. Taken together, our data provide evidence that multiple sites of plasticity within VOR pathways can rapidly shape motor performance in vivo. PMID:27157829

  7. Clinical characteristics and pathogenesis of cerebellar glioblastoma.

    Science.gov (United States)

    Takahashi, Yoshinobu; Makino, Keishi; Nakamura, Hideo; Hide, Takuichiro; Yano, Shigetoshi; Kamada, Hajime; Kuratsu, Jun-Ichi

    2014-11-01

    Cerebellar glioblastomas (GBMs) are rare, with neither their pathogenesis nor prognosis being completely understood. The present study aimed to clarify the clinical characteristics of cerebellar GBMs by comparison with supratentorial GBMs, focusing particularly on the pathogenesis. The clinical factors between cerebellar (n=10) and supratentorial (n=216) GBMs were compared. Additionally, p53 and epidermal growth factor receptor (EGFR) levels were investigated in six patients by immunostaining as well as the isocitrate dehydrogenase 1 (IDH1) status of five patients by direct sequencing. Eight males and two females participated in the present study, the mean age at diagnosis was 56.6 years and the range 37-75 years. Four patients presented with hydrocephalus and one with brainstem involvement, and two patients were diagnosed with neurofibromatosis type 1. Two patients had previously received radiotherapy, eight patients received postoperative radiotherapy and seven chemotherapy. The mean Karnofsky performance status (KPS) score was lower in patients with cerebellar GBMs compared to those with supratentorial GBM; however, the survival times did not differ between the two groups. All of the cases of six cerebellar GBMs were p53‑positive and EGFR‑negative, as detected by immunostaining, consistent with secondary GBM. However, no IDH1 mutations were detected in any of the five cases of cerebellar GBMs analyzed, indicating that these tumors were not of the secondary type. The KPS score with cerebellar GBMs may be lower due to hydrocephalus, which was ameliorated by surgery but may have impacted the survival rate. It was confirmed that cerebellar GBMs were identical to supratentorial GBMs with respect to its clinical features, with the possible exception of the KPS score. The present study's genetic analyses indicated that cerebellar GBMs may develop via a pathway different from that of either primary or secondary GBM. PMID:25199771

  8. Topography of Purkinje cells and other calbindin-immunoreactive cells within adult and hatchling turtle cerebellum.

    Science.gov (United States)

    Ariel, Michael; Ward, Kyle C; Tolbert, Daniel L

    2009-12-01

    The turtle's cerebellum (Cb) is an unfoliated sheet, so the topography of its entire cortex can be easily studied physiologically by optical recordings. However, unlike the mammalian Cb, little is known about the topography of turtle Purkinje cells (PCs). Here, topography was examined using calbindin-D(28K) immunohistochemistry of adult and hatchling turtles (Trachemys scripta elegans, 2.5-15 cm carapace length). Each Cb was flattened between two Sylgard sheets and fixed in paraformaldehyde. Sections (52 microm thick) were cut parallel to the flattened cortex (tangential), resulting in calbindin-immunolabeled PCs being localized to three to six sections for each turtle. PC position and size were quantified using Neurolucida Image Analysis system. Although hatchling Cb were medial-laterally narrower (3.0 vs. 6.5 mm) and rostral-caudally shorter (2.5 vs. 5.5 mm) than adult Cb, both averaged near 15,000 PCs distributed uniformly. Hatchling PCs were smaller than adult PCs (178 vs. 551 microm(2)) and more densely packed (2,180 vs. 625 cells/mm(2)). Calbindin immunoreactivity also labeled non-PCs along the Cb's marginal rim and its caudal pole. Many of these were very small (22.9 microm(2)) ovoid-shaped cells clustered together, possibly proliferating external granule layer cells. Other labeled cells were larger and fusiform-shaped (12.6 x 33.4 microm) adjacent to inner granule cells along the marginal rim, suggestive of migrating cells. It is not known whether these are new neurons being generated within the adult and hatchling Cb and if they connect to efferent and afferent paths. Based on these anatomical findings, we suggest that unique physiological features may exist along the rim of the turtle Cb.

  9. Pediatric Neurocutaneous Syndromes with Cerebellar Involvement.

    Science.gov (United States)

    Bosemani, Thangamadhan; Huisman, Thierry A G M; Poretti, Andrea

    2016-08-01

    Neurocutaneous syndromes encompasses a broad group of genetic disorders with different clinical, genetic, and pathologic features that share developmental lesions of the skin as well as central and peripheral nervous system. Cerebellar involvement has been shown in numerous types of neurocutaneous syndrome. It may help or be needed for the diagnosis and to explain the cognitive and behavioral phenotype of affected children. This article describes various types of neurocutaneous syndrome with cerebellar involvement. For each neurocutaneous disease or syndrome, clinical features, genetic, neuroimaging findings, and the potential role of the cerebellar involvement is discussed. PMID:27423801

  10. CT findings in cerebellar hemangioblastomas

    Energy Technology Data Exchange (ETDEWEB)

    Heiss, E.; Albert, F.

    1982-02-01

    The computed tomographic (CT) findings in 16 personal cases of cerebellar hemangioblastomas are presented. Accordings to other reports in the literature, three-quarters of the tumours were cystic, containing a small mural nodule, whereas the others were predominantly solid. By CT scan the cystic tumours were always identified as roundish or oval space-occupying lesions, sharply demarcated from the surrounding tissue. The solid portion of these tumours, projecting into the cystic part, was delineated more precisely by contrast enhancement, but sometimes escaped identification. On the contrary, even after contrast enhancement the predominantly solid tumours could not be clearly identified as hemangioblastomas. Calcification could not be demonstrated. Additional angiographic investigations were imperative in order to establish the diagnosis, besides visualizing further hypervascular nodules of hemangioblastoma, which CT scanning failed to reveal.

  11. Cerebellar mutism: review of the literature

    DEFF Research Database (Denmark)

    Gudrunardottir, Thora; Sehested, Astrid; Juhler, Marianne;

    2011-01-01

    Cerebellar mutism is a common complication of posterior fossa surgery in children. This article reviews current status with respect to incidence, anatomical substrate, pathophysiology, risk factors, surgical considerations, treatment options, prognosis and prevention....

  12. Cerebellar Involvement in Ataxia and Generalized Epilepsy

    NARCIS (Netherlands)

    L. Kros (Lieke)

    2015-01-01

    markdownabstract__Abstract__ The work described in this thesis was performed in order to elucidate the role of different cerebellar modules in ataxia and generalized epilepsy using various techniques including in vivo electrophysiology, optogenetics, pharmacological interventions, immunohistology a

  13. Cerebellar mutism: review of the literature

    DEFF Research Database (Denmark)

    Gudrunardottir, Thora; Sehested, Astrid; Juhler, Marianne;

    2011-01-01

    Cerebellar mutism is a common complication of posterior fossa surgery in children. This article reviews current status with respect to incidence, anatomical substrate, pathophysiology, risk factors, surgical considerations, treatment options, prognosis and prevention.......Cerebellar mutism is a common complication of posterior fossa surgery in children. This article reviews current status with respect to incidence, anatomical substrate, pathophysiology, risk factors, surgical considerations, treatment options, prognosis and prevention....

  14. Cholesterol overload impairing cerebellar function: the promise of natural products.

    Science.gov (United States)

    El-Sayyad, Hassan I H

    2015-05-01

    The cerebellum is the part of the brain most involved in controlling motor and cognitive function. The surface becomes convoluted, forming folia that have a characteristic internal structure of three layers including molecular, Purkinje cell, and granular layer. This complex neural network gives rise to a massive signal-processing capability. Cholesterol is a major constituent, derived by de novo synthesis and the blood-brain barrier. Cholesterol is tightly regulated between neurons and glia-that is, astrocytes, microglia, and oligodendrocytes-and is essential for normal brain development. The axon is wrapped by myelin (cholesterol, phospholipids, and glycosphingolipids) and made up of membranes of oligodendrocytes, separated by periodic gaps in the myelin sheath, called nodes of Ranvier. Hypercholesterolemia is associated with increased oxidative stress and the development of neurotoxicity and Alzheimer's disease. Treatment with natural products has been found to support improved brain function and reduce low-density-lipoprotein cholesterol level. Fish oil is one such product; among the many plant products are: Morus alba leaves, fruit, and bark; pomegranate fruit and peel; Barley β - glucans; date palm; and Allium sativum. The therapeutic potential was discussed in relation with the antilipidemic drugs, statins (HMG-CoA reductase inhibitors).

  15. Intraocular lens alignment from an en face optical coherence tomography image Purkinje-like method

    Science.gov (United States)

    Sun, Mengchan; de Castro, Alberto; Ortiz, Sergio; Perez-Merino, Pablo; Birkenfeld, Judith; Marcos, Susana

    2014-06-01

    Measurement of intraocular lens (IOL) alignment implanted in patients in cataract surgery is important to understand their optical performance. We present a method to estimate tilt and decentration of IOLs based on optical coherence tomography (OCT) images. En face OCT images show Purkinje-like images that correspond to the specular reflections from the corneal and IOL surfaces. Unlike in standard Purkinje-imaging, the tomographic nature of OCT allows unequivocal association of the reflection with the corresponding surface. The locations of the Purkinje-like images are linear combinations of IOL tilt, IOL decentration, and eye rotation. The weighting coefficients depend on the individual anterior segment geometry, obtained from the same OCT datasets. The methodology was demonstrated on an artificial model eye with set amounts of lens tilt and decentration and five pseudophakic eyes. Measured tilt and decentration in the artificial eye differed by 3.7% and 0.9%, respectively, from nominal values. In patients, average IOL tilt and decentration from Purkinje were 3.30±4.68 deg and 0.16±0.16 mm, respectively, and differed on average by 0.5 deg and 0.09 mm, respectively, from direct measurements on distortion-corrected OCT images. Purkinje-based methodology from anterior segment en face OCT imaging provided, therefore, reliable measurements of IOL tilt and decentration.

  16. Nerve growth factor enhances DNA synthesis in cultured cerebellar neuroblasts.

    Science.gov (United States)

    Confort, C; Charrasse, S; Clos, J

    1991-10-01

    The cerebellar neuroblasts in primary cultures from five-day-old rats bore NGF receptor immunoreactivity, suggesting a potential responsive to NGF. At low plating density, NGF was found to enhance DNA synthesis in these cells in a dose-dependent manner. As these cells synthesize NGF, one possibility to account for the lack of response of neuroblasts plated at high density is that the amount of endogenous trophic agent produced in this culture condition is sufficient to ensure an optimal effect. The results demonstrate that premitotic neuroblasts in the CNS, as well postmitotic neurons, are responsive to NGF. At the early stage of its development, the cerebellum therefore appears to be a very good autocrine model of NGF action. PMID:1661619

  17. Nerve growth factor enhances DNA synthesis in cultured cerebellar neuroblasts.

    Science.gov (United States)

    Confort, C; Charrasse, S; Clos, J

    1991-10-01

    The cerebellar neuroblasts in primary cultures from five-day-old rats bore NGF receptor immunoreactivity, suggesting a potential responsive to NGF. At low plating density, NGF was found to enhance DNA synthesis in these cells in a dose-dependent manner. As these cells synthesize NGF, one possibility to account for the lack of response of neuroblasts plated at high density is that the amount of endogenous trophic agent produced in this culture condition is sufficient to ensure an optimal effect. The results demonstrate that premitotic neuroblasts in the CNS, as well postmitotic neurons, are responsive to NGF. At the early stage of its development, the cerebellum therefore appears to be a very good autocrine model of NGF action.

  18. The volume of Purkinje cells decreases in the cerebellum of acrylamide-intoxicated rats, but no cells are lost

    DEFF Research Database (Denmark)

    Larsen, Jytte Overgaard; Tandrup, T; Braendgaard, H

    1994-01-01

    The effects of acrylamide intoxication on the numbers of granule and Purkinje cells and the volume of Purkinje cell perikarya have been evaluated with stereological methods. The analysis was carried out in the cerebella of rats that had received a dose of 33.3 mg/kg acrylamide, twice a week, for 7...

  19. Fetal MRI and antenatal diagnosis of unilateral cerebellar hypoplasia

    Directory of Open Access Journals (Sweden)

    Houda El Mhabrech

    2015-03-01

    Full Text Available Focal cerebellar hypoplasia is restricted to one cerebellar hemisphere or to the vermis. Prenatal diagnosis of unilateral cerebellar hypoplasia is possible by the use of ultrasound and MRI. Familiarity with the prenatal MRI findings is essential to recognize cerebellar pathologies accurately and prospectively. We present US and MRI findings in a fetus with cerebellar malformation at 20 weeks gestation. The goal of our case report is to present the fetal MRI findings of unilateral cerebellar hypoplasia, to discuss the value of fetal MRI in the early diagnoses of this malformation and to summarize the current main stream literature concerning the etiology.

  20. Bilateral Cerebellar Cortical Dysplasia without Other Malformations: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Jung Seok; Ahn Kook Jin; Kim, Jee Young; Lee, Sun Jin; Park, Jeong Mi [Catholic University Yeouido St. Mary' s Hospital, College of Medicine, Seoul (Korea, Republic of)

    2010-06-15

    Recent advances in MRI have revealed congenital brain malformations and subtle developmental abnormalities of the cerebral and cerebellar cortical architecture. Typical cerebellar cortical dysplasia as a newly categorized cerebellar malformation, has been seen in patients with Fukuyama congenital muscular dystrophy. Cerebellar cortical dysplasia occurs at the embryonic stage and is often observed in healthy newborns. It is also incidentally and initially detected in adults without symptoms. To the best of our knowledge, cerebellar dysplasia without any related disorders is very rare. We describe the MRI findings in one patient with disorganized foliation of both cerebellar hemispheres without a related disorder or syndrome

  1. Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

    Science.gov (United States)

    Turner, Jill R.; Ortinski, Pavel I.; Sherrard, Rachel M.

    2016-01-01

    Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum. PMID:21562921

  2. Development of motor coordination and cerebellar structure in male and female rat neonates exposed to hypergravity

    Science.gov (United States)

    Nguon, K.; Ladd, B.; Baxter, M. G.; Sajdel-Sulkowska, E. M.

    2006-01-01

    We previously reported that the developing rat cerebellum is affected by exposure to hypergravity. In the present study, we explored the hypothesis that the changes in cerebellar structure in hypergravity-exposed rat neonates may affect their motor coordination. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravitational loading. To test this hypothesis, we compared motor behavior, cerebellar structure, and protein expression in rat neonates exposed to 1.5 1.75G on a 24-ft centrifuge daily for 22.5 h starting on gestational day (G) 10, through birth on G22/G23 and through postnatal day (P) 21. Exposure to hypergravity impacted the neurodevelopmental process as indicated by: (1) impaired righting response on P3, more than doubling the righting time at 1.75G, and (2) delayed onset of the startle response by one day, from P9 in controls to P10 in hypergravity-exposed pups. Hypergravity exposure resulted in impaired motor functions as evidenced by performance on a rotarod on P21; the duration of the stay on the rotarod recorded for 1.75G pups of both sexes was one tenth that of the stationary control (SC) pups. These changes in motor behavior were associated with cerebellar changes: (1) cerebellar mass on P6 was decreased by 7.5% in 1.5G-exposed male pups, 27.5% in 1.75G-exposed male pups, 17.5% in 1.5G-exposed female pups, and 22.5% in 1.75G female pups and (2) changes in the expression of glial and neuronal proteins. The results of this study suggest that perinatal exposure to hypergravity affects cerebellar development as evidenced by decreased cerebellar mass and altered cerebellar protein expression; cerebellar changes observed in hypergravity-exposed rat neonates are associated with impaired motor behavior. Furthermore, the response to hypergravity appears to be different in male and female neonates. If one accepts that the hypergravity paradigm is a useful animal model with which to predict those biological processes

  3. Neuronal inhibition of astroglial cell proliferation is membrane mediated

    OpenAIRE

    1987-01-01

    Previously we have used a microwell tissue culture assay to show that early postnatal mouse cerebellar astroglia have a flattened morphology and proliferate rapidly when they are cultured in the absence of neurons, but develop specific cell-cell contacts and undergo morphological differentiation when they are co-cultured with purified granule neurons (Hatten, M. E., 1985, J. Cell Biol., 100:384-396). In these studies of cell binding between neurons and astroglia, measurement with light and fl...

  4. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred

    Science.gov (United States)

    Gulsuner, Suleyman; Tekinay, Ayse Begum; Doerschner, Katja; Boyaci, Huseyin; Bilguvar, Kaya; Unal, Hilal; Ors, Aslihan; Onat, O. Emre; Atalar, Ergin; Basak, A. Nazli; Topaloglu, Haluk; Kansu, Tulay; Tan, Meliha; Tan, Uner; Gunel, Murat; Ozcelik, Tayfun

    2011-01-01

    The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1–13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans. PMID:21885617

  5. Histopathological and Behavioral Assessment of Toxin-Produced Cerebellar Lesion: A Potent Model for Cell Transplantation Studies in The Cerebellum

    Directory of Open Access Journals (Sweden)

    Mohammad Amin Edalatmanesh

    2014-04-01

    Full Text Available cognition, learning and memory functions. This study presents a permanent model of a toxin produced cerebellar lesion characterized according to contemporary motor and cognitive abnormalities. Materials and Methods: In this experimental study, slow administration of quinolinic acid (QA, 5 μl of 200 μmol, 1 μl/minute in the right cerebellar hemisphere (lobule VI caused noticeable motor and cognitive disturbances along with cellular degeneration in all treated animals. We assessed behavioral and histopathological studies over ten weeks after QA treatment. The data were analyzed with ANOVA and the student’s t test. Results: The QA treated group showed marked motor learning deficits on the rotating rod test (p≤0.0001, locomotor asymmetry on the cylinder test (p≤0.0001, dysmetria on the beam balance test (p≤0.0001, abnormalities in neuromuscular strength on the hang wire test (p≤0.0001, spatial memory deficits in the Morris water maze (MWM, p≤0.001 and fear conditioned memory on the passive avoidance test (p≤0.01 over a ten-week period compared with the control animals. Histopathological analysis showed loss of Purkinje cells (p≤0.001 and granular cell density (p≤0.0001 in the lesioned hemisphere of the cerebellum. Conclusion: Results of the present study show that QA can remove numerous cells which respond to this toxin in hemispheric lobule VI and thus provide a potential model for functional and cell-based studies.

  6. Nitric oxide regulates input specificity of long-term depression and context dependence of cerebellar learning.

    Directory of Open Access Journals (Sweden)

    Hideaki Ogasawara

    2007-01-01

    Full Text Available Recent studies have shown that multiple internal models are acquired in the cerebellum and that these can be switched under a given context of behavior. It has been proposed that long-term depression (LTD of parallel fiber (PF-Purkinje cell (PC synapses forms the cellular basis of cerebellar learning, and that the presynaptically synthesized messenger nitric oxide (NO is a crucial "gatekeeper" for LTD. Because NO diffuses freely to neighboring synapses, this volume learning is not input-specific and brings into question the biological significance of LTD as the basic mechanism for efficient supervised learning. To better characterize the role of NO in cerebellar learning, we simulated the sequence of electrophysiological and biochemical events in PF-PC LTD by combining established simulation models of the electrophysiology, calcium dynamics, and signaling pathways of the PC. The results demonstrate that the local NO concentration is critical for induction of LTD and for its input specificity. Pre- and postsynaptic coincident firing is not sufficient for a PF-PC synapse to undergo LTD, and LTD is induced only when a sufficient amount of NO is provided by activation of the surrounding PFs. On the other hand, above-adequate levels of activity in nearby PFs cause accumulation of NO, which also allows LTD in neighboring synapses that were not directly stimulated, ruining input specificity. These findings lead us to propose the hypothesis that NO represents the relevance of a given context and enables context-dependent selection of internal models to be updated. We also predict sparse PF activity in vivo because, otherwise, input specificity would be lost.

  7. Metabolic anatomy of paraneoplastic cerebellar degeneration

    International Nuclear Information System (INIS)

    Eleven patients with acquired cerebellar degeneration (10 of whom had paraneoplastic cerebellar degeneration [PCD]) were evaluated using neuropsychological tests and 18F-fluorodeoxyglucose/positron emission tomography to (1) quantify motor, cognitive, and metabolic abnormalities; (2) determine if characteristic alterations in the regional cerebral metabolic rate for glucose (rCMRGlc) are associated with PCD; and (3) correlate behavioral and metabolic measures of disease severity. Eighteen volunteer subjects served as normal controls. Although some PCD neuropsychological test scores were abnormal, these results could not, in general, be dissociated from the effects of dysarthria and ataxia. rCMRGlc was reduced in patients with PCD (versus normal control subjects) in all regions except the brainstem. Analysis of patient and control rCMRGlc data using a mathematical model of regional metabolic interactions revealed two metabolic pattern descriptors, SSF1 and SSF2, which distinguished patients with PCD from normal control subjects; SSF2, which described a metabolic coupling between cerebellum, cuneus, and posterior temporal, lateral frontal, and paracentral cortex, correlated with quantitative indices of cerebellar dysfunction. Our inability to document substantial intellectual impairment in 7 of 10 patients with PCD contrasts with the 50% incidence of dementia in PCD reported by previous investigators. Widespread reductions in PCD rCMRGlc may result from the loss of cerebellar efferents to thalamus and forebrain structures, a reverse cerebellar diaschisis

  8. Oculomotor studies of cerebellar function in autism.

    Science.gov (United States)

    Nowinski, Caralynn V; Minshew, Nancy J; Luna, Beatriz; Takarae, Yukari; Sweeney, John A

    2005-11-15

    Histopathological, neuroimaging and genetic findings indicate cerebellar abnormalities in autism, but the extent of neurophysiological dysfunction associated with those findings has not been systematically examined. Suppression of intrusive saccades (square wave jerks) and the ability to sustain eccentric gaze, two phenomena requiring intact cerebellar function, were examined in 52 high-functioning individuals with autism and 52 age- and IQ-matched healthy subjects during visual fixation of static central and peripheral targets. Rates of intrusive saccades were not increased in autism during visual fixation, and foveopetal ocular drift was also not increased when subjects held an eccentric gaze. The absence of gross disturbances of visual fixation associated with cerebellar disease in individuals with autism, such as increased square wave jerk rates and foveopetal drift when holding eccentric gaze, indicates that the functional integrity of cerebellar--brainstem networks devoted to oculomotor control is preserved in autism despite reported anatomic variations. However, increased amplitude of intrusive saccades and reduced latency of target refixation after intrusive saccades were observed in individuals with autism, especially when subjects maintained fixation of remembered target locations without sensory guidance. The atypical metrics of intrusive saccades that were observed may be attributable to faulty functional connectivity in cortico-cerebellar networks. PMID:16214219

  9. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Genetics Home Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/ ... Open All Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

  10. Changes in cerebellar activity and inter-hemispheric coherence accompany improved reading performance following Quadrato Motor Training

    Science.gov (United States)

    Ben-Soussan, Tal Dotan; Avirame, Keren; Glicksohn, Joseph; Goldstein, Abraham; Harpaz, Yuval; Ben-Shachar, Michal

    2014-01-01

    Dyslexia is a multifactorial reading deficit that involves multiple brain systems. Among other theories, it has been suggested that cerebellar dysfunction may be involved in dyslexia. This theory has been supported by findings from anatomical and functional imaging. A possible rationale for cerebellar involvement in dyslexia could lie in the cerebellum’s role as an oscillator, producing synchronized activity within neuronal networks including sensorimotor networks critical for reading. If these findings are causally related to dyslexia, a training regimen that enhances cerebellar oscillatory activity should improve reading performance. We examined the cognitive and neural effects of Quadrato Motor Training (QMT), a structured sensorimotor training program that involves sequencing of motor responses based on verbal commands. Twenty-two adult Hebrew readers (12 dyslexics and 10 controls) were recruited for the study. Using Magnetoencephalography (MEG), we measured changes in alpha power and coherence following QMT in a within-subject design. Reading performance was assessed pre- and post-training using a comprehensive battery of behavioral tests. Our results demonstrate improved performance on a speeded reading task following one month of intensive QMT in both the dyslexic and control groups. Dyslexic participants, but not controls, showed significant increase in cerebellar oscillatory alpha power following training. In addition, across both time points, inter-hemispheric alpha coherence was higher in the dyslexic group compared to the control group. In conclusion, the current findings suggest that the combination of motor and language training embedded in QMT increases cerebellar oscillatory activity in dyslexics and improves reading performance. These results support the hypothesis that the cerebellum plays a role in skilled reading, and begin to unravel the underlying mechanisms that mediate cerebellar contribution in cognitive and neuronal augmentation. PMID

  11. Changes in cerebellar activity and inter-hemispheric coherence accompany improved reading performance following Quadrato Motor Training

    Directory of Open Access Journals (Sweden)

    Tal Dotan Ben-Soussan

    2014-05-01

    Full Text Available Dyslexia is a multifactorial reading deficit that involves multiple brain systems. Among other theories, it has been suggested that cerebellar dysfunction may be involved in dyslexia. This theory has been supported by findings from anatomical and functional imaging. A possible rationale for cerebellar involvement in dyslexia could lie in the cerebellum’s role as an oscillator, producing synchronized activity within neuronal networks including sensorimotor networks critical for reading. If these findings are causally related to dyslexia, a training regimen that enhances cerebellar oscillatory activity should improve reading performance. We examined the cognitive and neural effects of Quadrato Motor Training (QMT, a structured sensorimotor training program that involves sequencing of motor responses based on verbal commands. Twenty-two adult Hebrew readers (12 dyslexics and 10 controls were recruited for the study. Using Magnetoencephalography (MEG, we measured changes in alpha power and coherence following QMT in a within-subject design. Reading performance was assessed pre- and post-training using a comprehensive battery of behavioral tests. Our results demonstrate improved performance on a speeded reading task following one month of intensive QMT in both the dyslexic and control groups. Dyslexic participants, but not controls, showed significant increase in cerebellar oscillatory alpha power following training. In addition, across both time points, inter-hemispheric alpha coherence was higher in the dyslexic group compared to the control group. In conclusion, the current findings suggest that the combination of motor and language training embedded in QMT increases cerebellar oscillatory activity in dyslexics and improves reading performance. These results support the hypothesis that the cerebellum plays a role in skilled reading, and begin to unravel the underlying mechanisms that mediate cerebellar contribution in cognitive and neuronal

  12. Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults.

    Science.gov (United States)

    Cohen, Martin; Rasser, Paul E; Peck, Greg; Carr, Vaughan J; Ward, Philip B; Thompson, Paul M; Johnston, Patrick; Baker, Amanda; Schall, Ulrich

    2012-04-01

    Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.

  13. Nitric oxide damages neuronal mitochondria and induces apoptosis in neurons

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The cytotoxic effect of nitric oxide on primarily cultured rat cerebellar granule cells was studied,and the mechanisms were discussed.The results showed that nitric oxide donor S-nitroso-N-acetyl-penicillamine (SNAP; 500 μmol/L) could induce apoptosis in immature cultures of cerebellar granule cells.Flow cytometry and HPLC analyses revealed that after treatment with SNAP,the mitochondrial transmembrane potential and the cellular ATP content decreased significantly.Nitric oxide scavenger hemoglobin could effectively prevent the neuronal mitochondria from dysfunction and attenuate apoptosis.The results suggested that nitric oxide activated the apoptotic program by inhibiting the activity of mitochondrial respiratory chain and thus decreasing the cellular ATP content.

  14. Landmark based shape analysis for cerebellar ataxia classification and cerebellar atrophy pattern visualization

    Science.gov (United States)

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules.

  15. Anomalous Cerebellar Anatomy in Chinese Children with Dyslexia

    OpenAIRE

    Yang, Ying-Hui; Yang, Yang; Chen, Bao-Guo; Zhang, Yi-Wei; Bi, Hong-Yan

    2016-01-01

    The cerebellar deficit hypothesis for developmental dyslexia claims that cerebellar dysfunction causes the failures in the acquisition of visuomotor skills and automatic reading and writing skills. In people with dyslexia in the alphabetic languages, the abnormal activation and structure of the right or bilateral cerebellar lobes have been identified. Using a typical implicit motor learning task, however, one neuroimaging study demonstrated the left cerebellar dysfunction in Chinese children ...

  16. Sub-Lethal Dose of Shiga Toxin 2 from Enterohemorrhagic Escherichia coli Affects Balance and Cerebellar Cytoarchitecture

    Science.gov (United States)

    Pinto, Alipio; Cangelosi, Adriana; Geoghegan, Patricia A.; Tironi-Farinati, Carla; Brener, Gabriela J.; Goldstein, Jorge

    2016-01-01

    Shiga toxin producing Escherichia coli may damage the central nervous system before or concomitantly to manifested hemolytic–uremic syndrome symptoms. The cerebellum is frequently damaged during this syndrome, however, the deleterious effects of Shiga toxin 2 has never been integrally reported by ultrastructural, physiological and behavioral means. The aim of this study was to determine the cerebellar compromise after intravenous administration of a sub-lethal dose of Shiga toxin 2 by measuring the cerebellar blood–brain barrier permeability, behavioral task of cerebellar functionality (inclined plane test), and ultrastructural analysis (transmission electron microscope). Intravenous administration of vehicle (control group), sub-lethal dose of 0.5 and 1 ηg of Stx2 per mouse were tested for behavioral and ultrastructural studies. A set of three independent experiments were performed for each study (n = 6). Blood–brain barrier resulted damaged and consequently its permeability was significantly increased. Lower scores obtained in the inclined plane task denoted poor cerebellar functionality in comparison to their controls. The most significant lower score was obtained after 5 days of 1 ηg of toxin administration. Transmission electron microscope micrographs from the Stx2-treated groups showed neurons with a progressive neurodegenerative condition in a dose dependent manner. As sub-lethal intravenous Shiga toxin 2 altered the blood brain barrier permeability in the cerebellum the toxin penetrated the cerebellar parenchyma and produced cell damaged with significant functional implications in the test balance. PMID:26904009

  17. Sub-Lethal Dose of Shiga toxin 2 from Enterohemorrhagic Escherichia coli Affects Balance and Cerebellar Cythoarquitecture.

    Directory of Open Access Journals (Sweden)

    Luciana eD’Alessio

    2016-02-01

    Full Text Available Shiga toxin producing Escherichia coli may damage the central nervous system before or concomitantly to manifested hemolytic uremic syndrome symptoms. The cerebellum is frequently damaged during this syndrome, however the deleterious effects of Shiga toxin 2 has never been integrally reported by ultrastructural, physiological and behavioral means. The aim of this study was to determine the cerebellar compromise after intravenous administration of a sub-lethal dose of Shiga toxin 2 by measuring the cerebellar blood brain barrier permeability, behavioral task of cerebellar functionality (inclined plane test, and ultrastructural analysis (transmission electron microscope. Intravenous administration of vehicle (control group, sub-lethal dose of 0.5 ηg and 1 ηg of Stx2 per mouse were tested for behavioral and ultrastructural studies. A set of three independent experiments were performed for each study (n=6. Blood–Brain Barrier resulted damaged and consequently its permeability was significantly increased. Lower scores obtained in the inclined plane task denoted poor cerebellar functionality in comparison to their controls. The most significant lower score was obtained after 5 days of 1ηg of toxin administration. Transmission electron microscope micrographs from the Stx2-treated groups showed neurons with a progressive neurodegenerative condition in a dose dependent manner. As sub-lethal intravenous Shiga toxin 2 altered the blood brain barrier permeability in the cerebellum the toxin penetrated the cerebellar parenchyma and produced cell damaged with significant functional implications in the test balance.

  18. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression.

    Science.gov (United States)

    Gallimore, Andrew R; Aricescu, A Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins-glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)-regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process. PMID:26807999

  19. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression.

    Directory of Open Access Journals (Sweden)

    Andrew R Gallimore

    2016-01-01

    Full Text Available The expression of long-term depression (LTD in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins-glutamate receptor-interacting protein (GRIP and protein interacting with C kinase 1 (PICK1-regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

  20. Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.

    Science.gov (United States)

    Stefely, Jonathan A; Licitra, Floriana; Laredj, Leila; Reidenbach, Andrew G; Kemmerer, Zachary A; Grangeray, Anais; Jaeg-Ehret, Tiphaine; Minogue, Catherine E; Ulbrich, Arne; Hutchins, Paul D; Wilkerson, Emily M; Ruan, Zheng; Aydin, Deniz; Hebert, Alexander S; Guo, Xiao; Freiberger, Elyse C; Reutenauer, Laurence; Jochem, Adam; Chergova, Maya; Johnson, Isabel E; Lohman, Danielle C; Rush, Matthew J P; Kwiecien, Nicholas W; Singh, Pankaj K; Schlagowski, Anna I; Floyd, Brendan J; Forsman, Ulrika; Sindelar, Pavel J; Westphall, Michael S; Pierrel, Fabien; Zoll, Joffrey; Dal Peraro, Matteo; Kannan, Natarajan; Bingman, Craig A; Coon, Joshua J; Isope, Philippe; Puccio, Hélène; Pagliarini, David J

    2016-08-18

    The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease. PMID:27499294

  1. Cerebellar Expression of the Neurotrophin Receptor p75 in Naked-Ataxia Mutant Mouse

    Directory of Open Access Journals (Sweden)

    Maryam Rahimi Balaei

    2016-01-01

    Full Text Available Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2 mouse (nax—naked-ataxia mutant mouse correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc degeneration. Loss of Pcs in the nax cerebellum is compartmentalized and harmonized to the classic pattern of gene expression of the cerebellum in the wild type mouse. Usually, degeneration starts in the anterior and posterior zones and continues to the central and nodular zones of cerebellum. Studies have suggested that the p75 neurotrophin receptor (NTR plays a role in Pc degeneration; thus, in this study, we investigated the p75NTR pattern and protein expression in the cerebellum of the nax mutant mouse. Despite massive Pc degeneration that was observed in the nax mouse cerebellum, p75NTR pattern expression was similar to the HSP25 pattern in nax mice and comparable with wild type sibling cerebellum. In addition, immunoblot analysis of p75NTR protein expression did not show any significant difference between nax and wild type sibling (p > 0.5. In comparison with wild type counterparts, p75NTR pattern expression is aligned with the fundamental cytoarchitecture organization of the cerebellum and is unchanged in the nax mouse cerebellum despite the severe neurodevelopmental disorder accompanied with Pc degeneration.

  2. Impaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency.

    Science.gov (United States)

    Bao, S; Chen, L; Qiao, X; Knusel, B; Thompson, R F

    1998-01-01

    In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.

  3. Crossed cerebellar diaschisis in ischemic stroke

    DEFF Research Database (Denmark)

    Meneghetti, G; Vorstrup, S; Mickey, B;

    1984-01-01

    Seventy measurements of CBF were performed in 12 stroke patients by 133Xe inhalation and a rapidly rotating single photon emission computerized tomograph. CBF was measured every other day during the acute phase and at 2- and 6-month follow-up visits. A persistent contralateral cerebellar blood flow....... It is concluded from this serial study that crossed cerebellar diaschisis is a common finding in completed stroke. It is probably caused by disconnection of the corticopontine pathways, a disconnection that tends to persist. The phenomenon is in fact less variable than the stroke-related CBF changes...

  4. Paraneoplastic cerebellar dysfunction in Hodgkin's lymphoma

    Directory of Open Access Journals (Sweden)

    Kazi Sazzad Manir

    2015-01-01

    Full Text Available Paraneoplastic cerebellar degeneration (PCD is a rare presentation of Hodgkin's Lymphoma (HL manifests as acute/sub-acute nature. We report a case of 21 yr old male presented with acute cerebellar signs along with underlying HL.MRI brain was normal. CSF study was unremarkable. Patient was treated with six cycles of chemotherapy followed by radiotherapy. Neurological manifestations remarkably improved along with complete resolution of underlying HL. Anti-cancer therapy of underlying HL is the main strategy of treating associated PCD.

  5. An effective algorithm for the generation of patient-specific Purkinje networks in computational electrocardiology

    Science.gov (United States)

    Palamara, Simone; Vergara, Christian; Faggiano, Elena; Nobile, Fabio

    2015-02-01

    The Purkinje network is responsible for the fast and coordinated distribution of the electrical impulse in the ventricle that triggers its contraction. Therefore, it is necessary to model its presence to obtain an accurate patient-specific model of the ventricular electrical activation. In this paper, we present an efficient algorithm for the generation of a patient-specific Purkinje network, driven by measures of the electrical activation acquired on the endocardium. The proposed method provides a correction of an initial network, generated by means of a fractal law, and it is based on the solution of Eikonal problems both in the muscle and in the Purkinje network. We present several numerical results both in an ideal geometry with synthetic data and in a real geometry with patient-specific clinical measures. These results highlight an improvement of the accuracy provided by the patient-specific Purkinje network with respect to the initial one. In particular, a cross-validation test shows an accuracy increase of 19% when only the 3% of the total points are used to generate the network, whereas an increment of 44% is observed when a random noise equal to 20% of the maximum value of the clinical data is added to the measures.

  6. Segmental identity and cerebellar granule cell induction in rhombomere 1

    Directory of Open Access Journals (Sweden)

    Bell Esther

    2004-06-01

    Full Text Available Abstract Background Cerebellar granule cell precursors are specifically generated within the hindbrain segment, rhombomere 1, which is bounded rostrally by the midbrain/hindbrain isthmus and caudally by the boundary of the Hoxa2 expression domain. While graded signals from the isthmus have a demonstrable patterning role within this region, the significance of segmental identity for neuronal specification within rhombomere 1 is unexplored. We examined the response of granule cell precursors to the overexpression of Hoxa2, which normally determines patterns of development specific to the hindbrain. How much does the development of the cerebellum, a midbrain/hindbrain structure, reflect its neuromeric origin as a hindbrain segment? Results We show that a Gbx2-positive, Otx2-/Hoxa2-negative territory corresponding to rhombomere 1 forms prior to an identifiable isthmic organiser. Early global overexpression of Hoxa2 at embryonic day 0 has no effect on the expression of isthmic signalling molecules or the allocation of rhombomere 1 territory, but selectively results in the loss of granule cell markers at embryonic day 6 and the depletion of cell bodies from the external granule cell layer. By comparison the trochlear nucleus and locus coeruleus form normally in ventral rhombomere 1 under these conditions. Microsurgery, coupled with electroporation, to target Hoxa2 overexpression to rhombic lip precursors, reveals a profound, autonomous respecification of migration. Rhombic lip derivatives, normally destined to occupy the external granule cell layer, violate the cerebellar boundary to form a ventrolateral nucleus in a position comparable to that occupied by rhombic lip derived neurons in rhombomere 2. Conclusions Different overexpression strategies reveal that the recognition of migration cues by granule cell precursors is dependent on their identity as rhombomere 1 derivatives. Segmental patterning cues operate autonomously within the rhombic lip

  7. The Cerebellar Mutism Syndrome and Its Relation to Cerebellar Cognitive Function and the Cerebellar Cognitive Affective Disorder

    Science.gov (United States)

    Wells, Elizabeth M.; Walsh, Karin S.; Khademian, Zarir P.; Keating, Robert F.; Packer, Roger J.

    2008-01-01

    The postoperative cerebellar mutism syndrome (CMS), consisting of diminished speech output, hypotonia, ataxia, and emotional lability, occurs after surgery in up to 25% of patients with medulloblastoma and occasionally after removal of other posterior fossa tumors. Although the mutism is transient, speech rarely normalizes and the syndrome is…

  8. Cerebellar motor dysfunction in schizophrenia and psychosis risk: the importance of regional cerebellar analysis approaches

    Directory of Open Access Journals (Sweden)

    Jessica A Bernard

    2014-11-01

    Full Text Available Motor abnormalities in individuals with schizophrenia and those at-risk for psychosis are well documented. An accumulating body of work has also highlighted motor abnormalities related to cerebellar dysfunction in schizophrenia including eye-blink conditioning, timing, postural control, and motor learning. We have also recently found evidence for motor dysfunction in individuals at ultra high-risk for psychosis (1–3. This is particularly relevant as the cerebellum is thought to be central to the cognitive dysmetria model of schizophrenia, and these overt motor signs may point to more general cerebellar dysfunction in the etiology of psychotic disorders. While studies have provided evidence indicative of motor cerebellar dysfunction in at-risk populations and in schizophrenia, findings with respect to the cerebellum have been mixed. One factor potentially contributing to these mixed results is the whole-structure approach taken when investigating the cerebellum. In non-human primates there are distinct closed-loop circuits between the cerebellum, thalamus, and brain with motor and non-motor cortical regions. Recent human neuroimaging has supported this finding and indicates that there is a cerebellar functional topography (4, and this information is being missed with whole-structure approaches. Here, we review cerebellar motor dysfunction in individuals with schizophrenia and those at-risk for psychosis. We also discuss cerebellar abnormalities in psychosis, and the cerebellar functional topography. Because of the segregated functional regions of the cerebellum, we propose that it is important to look at the structure regionally in order to better understand its role in motor dysfunction in these populations. This is analogous to approaches taken with the basal ganglia, where each region is considered separately. Such an approach is necessary to better understand cerebellar pathophysiology on a macro-structural level with respect to the

  9. Ultrasonically detectable cerebellar haemorrhage in preterm infants.

    LENUS (Irish Health Repository)

    McCarthy, Lisa Kenyon

    2011-07-01

    To determine the frequency and pattern of cerebellar haemorrhage (CBH) on routine cranial ultrasound (cUS) imaging in infants of ≤32 weeks gestation, and to investigate how extremely preterm infants with CBH differ from those with severe intraventricular haemorrhage (IVH).

  10. Cerebellar cortical inhibition and classical eyeblink conditioning.

    Science.gov (United States)

    Bao, Shaowen; Chen, Lu; Kim, Jeansok J; Thompson, Richard F

    2002-02-01

    The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

  11. Improving cerebellar segmentation with statistical fusion

    Science.gov (United States)

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-03-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multiatlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non- Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

  12. Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models

    Directory of Open Access Journals (Sweden)

    Kung PJ

    2014-10-01

    Full Text Available Pin-Jui Kung,1,* Yu-Chen Tao,1,* Ho-Chiang Hsu,1 Wan-Ling Chen,1 Te-Hsien Lin,1 Donala Janreddy,2 Ching-Fa Yao,2 Kuo-Hsuan Chang,3 Jung-Yaw Lin,1 Ming-Tsan Su,1 Chung-Hsin Wu,1 Guey-Jen Lee-Chen,1 Hsiu-Mei Hsieh-Li1 1Department of Life Science, 2Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan; 3Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan *These authors contributed equally to this work Abstract: In spinocerebellar ataxia type 17 (SCA17, the expansion of a translated CAG repeat in the TATA box binding protein (TBP gene results in a long polyglutamine (polyQ tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment. Keywords: spinocerebellar ataxia type 17, TATA box binding protein, polyQ aggregation, indole and derivative, therapeutics

  13. Anti-Yo and anti-glutamic acid decarboxylase antibodies presenting in carcinoma of the uterus with paraneoplastic cerebellar degeneration: a case report

    Directory of Open Access Journals (Sweden)

    Panegyres Peter K

    2012-06-01

    Full Text Available Abstract Introduction Paraneoplastic cerebellar degeneration is a rare non-metastatic manifestation of malignancy. In this report, to the best of our knowledge we describe for the first time a diagnosis of paraneoplastic cerebellar degeneration several months prior to the diagnosis of clear carcinoma of the uterus. Case presentation A 75-year-old Caucasian woman manifested a rapidly progressive cerebellar syndrome with nystagmus, past-pointing, dysdiadochokinesis, dysarthria, truncal ataxia and titubation. The paraneoplastic cerebellar degeneration was associated with anti-Yo and anti-glutamic acid decarboxylase antibodies. 14-3-3 protein was detected in the cerebrospinal fluid. She was treated with intravenous immunoglobulin prior to laparotomy, hysterectomy and bilateral salpingoophorectomy. Our patient has survived for three years following diagnosis and treatment. Conclusions To the best of our knowledge this is the first report of an association of clear cell carcinoma of the uterus and paraneoplastic cerebellar degeneration with both anti-Yo and anti-glutamic acid decarboxylase antibodies. The findings imply that both antibodies contributed to the fulminating paraneoplastic cerebellar degeneration observed in our patient, and this was of such severity it resulted in the release of 14-3-3 protein in the cerebrospinal fluid, a marker of neuronal death.

  14. Do brainstem omnipause neurons terminate saccades?

    Science.gov (United States)

    Rucker, Janet C; Ying, Sarah H; Moore, Willa; Optican, Lance M; Büttner-Ennever, Jean; Keller, Edward L; Shapiro, Barbara E; Leigh, R John

    2011-09-01

    Saccade-generating burst neurons (BN) are inhibited by omnipause neurons (OPN), except during saccades. OPN activity pauses before saccade onset and resumes at the saccade end. Microstimulation of OPN stops saccades in mid-flight, which shows that OPN can end saccades. However, OPN pause duration does not correlate well with saccade duration, and saccades are normometric after OPN lesions. We tested whether OPN were responsible for stopping saccades both in late-onset Tay-Sachs, which causes premature saccadic termination, and in individuals with cerebellar hypermetria. We studied gaze shifts between two targets at different distances aligned on one eye, which consist of a disjunctive saccade followed by vergence. High-frequency conjugate oscillations during the vergence movements that followed saccades were present in all subjects studied, indicating OPN silence. Thus, mechanisms other than OPN discharge (e.g., cerebellar caudal fastigial nucleus-promoting inhibitory BN discharge) must contribute to saccade termination. PMID:21950975

  15. Early maternal deprivation in rats induces gender-dependent effects on developing hippocampal and cerebellar cells.

    Science.gov (United States)

    Llorente, Ricardo; Gallardo, Meritxell López; Berzal, Alvaro Llorente; Prada, Carmen; Garcia-Segura, Luis Miguel; Viveros, María-Paz

    2009-05-01

    Adult animals submitted to a single prolonged episode of maternal deprivation [24h, postnatal day 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. According to the neurodevelopmental theory, these behavioral deficits might be mediated by detrimental neurodevelopmental processes that might be associated, at least partially, with stress-induced corticosterone responses. In order to address this hypothesis, we have focused on the hippocampus and cerebellar cortex, two brain regions that show high density of glucocorticoid receptors, and analyzed possible neuronal and glial alterations by immunohistochemical techniques. To evaluate the presence of degenerated neurons we used Fluoro-Jade-C (FJ-C) staining and for the study of astrocytes we employed glial fibrillary acidic protein (GFAP). Within control animals, females showed significantly more GFAP positive cells than males and a trend towards more FJ-C positive cells. Maternal deprivation induced neuronal degeneration and astroglial changes in the hippocampus and cerebellar cortex of neonatal rats that, in general, were more marked in males. This differential effect may be attributable to a greater vulnerability of males to this kind of early environmental insult and/or to sex-dependent differences in the onset and/or progression of the effects. The present experimental procedure may be instrumental in elucidating sex-dependent mechanisms of neurodevelopmental psychiatric disorders with a basis in early environmental insults.

  16. Electropharmacological effects of berberine on canine cardiac Purkinje fibres and ventricular muscle and atrial muscle of the rabbit.

    OpenAIRE

    Riccioppo Neto, F.

    1993-01-01

    1. Conventional microelectrode techniques were used for intracellular recordings of the transmembrane electrical potentials, the effects of berberine were studied on canine cardiac Purkinje and ventricular muscle fibres and on rabbit atrial fibres. 2. Berberine (3-30 microM) increased in a concentration-dependent manner, the action potential duration (APD) in canine Purkinje and ventricular muscle without affecting other parameters of the action potential. 3. The berberine-induced enlargement...

  17. Cytotoxic CD8+ T cells and CD138+ plasma cells prevail in cerebrospinal fluid in non-paraneoplastic cerebellar ataxia with contactin-associated protein-2 antibodies

    Directory of Open Access Journals (Sweden)

    Melzer Nico

    2012-07-01

    Full Text Available Abstract Objective The purpose of this paper is to report a patient with otherwise unexplained cerebellar ataxia with serum antibodies against contactin-associated protein-2 (CASPR-2 and provide a detailed description of the composition of cellular infiltrates in the cerebrospinal fluid (CSF compared to the peripheral blood (PB. CASPR-2 antibodies strongly labeling axons of cerebellar granule neurons have recently been identified in sera from nine patients with otherwise unexplained progressive cerebellar ataxia with mild to severe cerebellar atrophy. Design This is a report of a single case. Methods The study methods used were neurologic examination, magnetic resonance imaging, fluorodeoxyglucose positron emisson tomography, lumbar puncture and multicolor flow-cytometry. Results A 23-year-old Caucasian male presented with a two-year history of a progressive cerebellar and brainstem syndrome. Magnetic resonance imaging (MRI showed pronounced cerebellar atrophy, especially of the medial parts of the hemispheres and the vermis. Cerebral fluorodeoxyglucose positron emission tomography (FDG-PET showed pronounced hypometabolism of the whole cerebellum. CASPR-2 antibodies were detected in the serum but not the CSF, and none of the staging and laboratory assessments revealed other causes of progressive cerebellar degeneration. Interestingly, flow-cytometry of the CSF as compared to the PB showed increased fractions of CD138+ plasma cells as well as human leukocyte antigen (HLA-DR+ CD8+ T cells suggesting that both B cells and CD8+ T cells were preferentially recruited to and activated within the CSF- (and putatively central nervous system (CNS- compartment. Conclusion We confirm the association of CASPR-2 serum antibodies with cerebellar ataxia and provide the first evidence for a combined humoral and cellular immune response in this novel antibody-associated inflammatory CNS disease.

  18. Vestibular efferent neurons project to the flocculus

    Science.gov (United States)

    Shinder, M. E.; Purcell, I. M.; Kaufman, G. D.; Perachio, A. A.

    2001-01-01

    A bilateral projection from the vestibular efferent neurons, located dorsal to the genu of the facial nerve, to the cerebellar flocculus and ventral paraflocculus was demonstrated. Efferent neurons were double-labeled by the unilateral injections of separate retrograde tracers into the labyrinth and into the floccular and ventral parafloccular lobules. Efferent neurons were found with double retrograde tracer labeling both ipsilateral and contralateral to the sites of injection. No double labeling was found when using a fluorescent tracer with non-fluorescent tracers such as horseradish peroxidase (HRP) or biotinylated dextran amine (BDA), but large percentages of efferent neurons were found to be double labeled when using two fluorescent substances including: fluorogold, microruby dextran amine, or rhodamine labeled latex beads. These data suggest a potential role for vestibular efferent neurons in modulating the dynamics of the vestibulo-ocular reflex (VOR) during normal and adaptive conditions.

  19. A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD machinery.

    Directory of Open Access Journals (Sweden)

    Kaisa Kyöstilä

    Full Text Available Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p(raw = 1.1x10(-7, p(genome = 7.5x10(-4. Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L, revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER-associated protein degradation (ERAD machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD-mediated neurodegenerative

  20. The damage of alcohol to cerebellar cells from primary cultured rats%酒精对原代培养大鼠小脑细胞的损害

    Institute of Scientific and Technical Information of China (English)

    许小林; 薛强

    2001-01-01

    原代培养的新生大鼠小脑颗粒神经元及小脑细胞经不同浓度的酒精进行处理,用倒置显微镜及四甲基偶氮唑蓝(MTT)法测定细胞存活率。结果酒精浓度在5~40 mmol/L时,细胞存活率呈剂量依赖性降低。酒精浓度增至160mmol/L时,颗粒神经元的存活率回升。提示酒精对原代培养大鼠小脑细胞有细胞毒性作用。在高浓度(160mmol/L)时,其对颗粒神经元毒性减小。%The cerebellar granule neurons and cerebellar cells from newborn primary cultured rats were treated with alcohol of different concentration. The cytotoxicity of alcohol on rats was observed. The survival rate of cells was detected by using an inverted microscope and MTT assay. Results showed that the survival rate of the rat cerebellar cells presented a dosage-dependent decrease when the concentration of the alcohol was from 5~40mmol/L, when the concentration reached 160mmol/L, the survival rate of rat cerebellar granule neurons rose again. This study suggests that alcohol has a cytotoxity to primary cultured rat cerebellar cells but at a high concentration its toxicity to cerebellar granule neurons of primary cultured rats is reduced.

  1. Coupling internal cerebellar models enhances online adaptation and supports offline consolidation in sensorimotor tasks

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste ePassot

    2013-07-01

    Full Text Available The cerebellum is thought to mediate sensorimotor adaptation through the acquisition of internal models of the body–environment interaction. These representations can be of two types, identified as forward and inverse models. The first predicts the sensory consequences of actions, while the second provides the correct commands to achieve desired state transitions. In this paper, we propose a composite architecture consisting of multiple cerebellar internal models to account for the adaptation performance of humans during sensorimotor learning. The proposed model takes inspiration from the cerebellar microcomplex circuit, and employs spiking neurons to process information. We investigate the intrinsic properties of the cerebellar circuitry subserving efficient adaptation properties, and we assess the complementary contributions of internal representations by simulating our model in a procedural adaptation task. Our simulation results suggest that the coupling of internal models enhances learning performance significantly (compared with independent forward and inverse models, and it allows for the reproduction of human adaptation capabilities. Furthermore, we provide a computational explanation for the performance improvement observed after one night of sleep in a wide range of sensorimotor tasks. We predict that internal model coupling is a necessary condition for the offline consolidation of procedural memories.

  2. Cell death in the Purkinje cells of the cerebellum of senescence accelerated mouse (SAMP(8)).

    Science.gov (United States)

    Zhu, Yonghong; Lee, Cleo C L; Lam, W P; Wai, Maria S M; Rudd, John A; Yew, David T

    2007-10-01

    The cerebella of SAMP(8) (accelerated aging mouse) and SAMR(1) controls were analyzed by Western Blotting of tyrosine hydroxylase and choline acetyltransferase, as well as by TUNEL and histological silver staining. Both tyrosine hydroxylase and choline acetyltransferase levels were higher in SAMR(1) than in SAMP(8). There was also an age-related decrease in enzyme levels in SAMP(8), with the reduction of tyrosine hydroxylase being more apparent. Concomitantly, there was an age-related increase of apoptosis in the medial neocerebellum and the vermis as revealed by TUNEL, with changes being significant in the SAMP(8) strain. Histologically, some Purkinje cells appeared to disappear during aging. Taken together, the data suggests that the aging SAMP(8) strain displays differential Purkinje cell death in the medial cerebellum and that some of the dying cells are likely to be catecholaminergic. PMID:17415677

  3. Evaluation of intraocular lens implant location in the eyeball basing on the Purkinje images

    Science.gov (United States)

    Jóźwik, A.; Siedlecki, D.; Zajac, M.

    2012-01-01

    Intraocular lens (IOL) is an artificial implant substituting natural crystalline lens which is non-transparent due to cataract. Incorrect location of the IOL in the eyeball (e.g. its shift or tilt) causes significant deterioration of patient's vision. The analysis of Purkinje images (i.e. reflections from successive refracting surfaces in the eye) enables to determine the real IOL location and thus helps in evaluating the retinal image quality. The experimental setup for Purkinje images recording consists of illuminator, composed of a number of infrared LEDs, telecentric lens and detector (CCD camera). Analysis of mutual position of particular reflections enables to evaluate the lens location in respect to the corneal axis. The actual measurements are realized on artificial eye model, what allows to estimate the precision of the algorithm applied in the calculations. In the future the experimental set-up will be adapted to measure the eyes of real patients.

  4. A toolbox to visually explore cerebellar shape changes in cerebellar disease and dysfunction

    Science.gov (United States)

    Abulnaga, S. Mazdak; Yang, Zhen; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi U.; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    The cerebellum plays an important role in motor control and is also involved in cognitive processes. Cerebellar function is specialized by location, although the exact topographic functional relationship is not fully understood. The spinocerebellar ataxias are a group of neurodegenerative diseases that cause regional atrophy in the cerebellum, yielding distinct motor and cognitive problems. The ability to study the region-specific atrophy patterns can provide insight into the problem of relating cerebellar function to location. In an effort to study these structural change patterns, we developed a toolbox in MATLAB to provide researchers a unique way to visually explore the correlation between cerebellar lobule shape changes and function loss, with a rich set of visualization and analysis modules. In this paper, we outline the functions and highlight the utility of the toolbox. The toolbox takes as input landmark shape representations of subjects' cerebellar substructures. A principal component analysis is used for dimension reduction. Following this, a linear discriminant analysis and a regression analysis can be performed to find the discriminant direction associated with a specific disease type, or the regression line of a specific functional measure can be generated. The characteristic structural change pattern of a disease type or of a functional score is visualized by sampling points on the discriminant or regression line. The sampled points are used to reconstruct synthetic cerebellar lobule shapes. We showed a few case studies highlighting the utility of the toolbox and we compare the analysis results with the literature.

  5. Supplementary motor area and presupplementary motor area: targets of basal ganglia and cerebellar output.

    Science.gov (United States)

    Akkal, Dalila; Dum, Richard P; Strick, Peter L

    2007-10-01

    We used retrograde transneuronal transport of neurotropic viruses in Cebus monkeys to examine the organization of basal ganglia and cerebellar projections to two cortical areas on the medial wall of the hemisphere, the supplementary motor area (SMA) and the pre-SMA. We found that both of these cortical areas are the targets of disynaptic projections from the dentate nucleus of the cerebellum and from the internal segment of the globus pallidus (GPi). On average, the number of pallidal neurons that project to the SMA and pre-SMA is approximately three to four times greater than the number of dentate neurons that project to these cortical areas. GPi neurons that project to the pre-SMA are located in a rostral, "associative" territory of the nucleus, whereas GPi neurons that project to the SMA are located in a more caudal and ventral "sensorimotor" territory. Similarly, dentate neurons that project to the pre-SMA are located in a ventral, "nonmotor" domain of the nucleus, whereas dentate neurons that project to the SMA are located in a more dorsal, "motor" domain. The differential origin of subcortical projections to the SMA and pre-SMA suggests that these cortical areas are nodes in distinct neural systems. Although both systems are the target of outputs from the basal ganglia and the cerebellum, these two cortical areas seem to be dominated by basal ganglia input. PMID:17913900

  6. ROLE OF PURKINJE FIBERS IN MAINTENANCE ANDTERMINATION OF LONG-DURATION VENTRICULARFIBRILLATION

    Institute of Scientific and Technical Information of China (English)

    金奇; 沈卫峰; 吴立群

    2011-01-01

    Long-duration ventricular fibrillation (LDVF) often occurring out-of-hospital has been presented several minutes before electrical shocks. It is important to understand the mechanism by which LDVF is maintained and defibrillated. Purkinje fibers (PFs) have been demonstrated to play a key role in the onset of certain types of ventricular fibrillation. In this review, we discuss the electrophysiological difference between PFs and working myocardium, and the role of the PFs in the maintenance and termination o...

  7. Isolated rhomboencephalosynapsis – a rare cerebellar anomaly

    International Nuclear Information System (INIS)

    Rhomboencephalosynapsis (RES, RS) is a unique entity usually recognized in infancy based on neuroimaging. Cerebellar fusion and absence of cerebellar vermis is often associated with supratentorial findings. Since now there are about 50 cases described worldwide, with approximately 36 patients diagnosed by MRI. The authors present the first in Poland case of this uncommon malformation and review the literature. The authors describe a 28-month-old-girl with microcephaly and proper psychomotor development. The family history was unrelevant. Based on MRI the congenital malformation of posterior fossa-rhombencephalosynapsis was confirmed Presented patient is a typical example of MRI usefulness especially in patients with RES. RES symptoms are mild and that is why the diagnosis is usually made only in adulthood

  8. Cerebellar ataxia as presenting feature of hypothyroidism.

    Science.gov (United States)

    Kotwal, Suman Kumar; Kotwal, Shalija; Gupta, Rohan; Singh, Jang Bhadur; Mahajan, Annil

    2016-04-01

    Symptoms and signs of the hypothyroidism vary in relation to the magnitude and acuteness of the thyroid hormone deficiency. The usual clinical features are constipation, fatigue, cold intolerance and weight gain. Rarely it can present with neurologic problems like reversible cerebellar ataxia, dementia, peripheral neuropathy, psychosis and coma. Hypothyroidism should be suspected in all cases of ataxia, as it is easily treatable. A 40 year-old male presented with the history facial puffiness, hoarseness of voice and gait-ataxia. Investigations revealed frank primary hypothyroidism. Anti-TPO antibody was positive. Thyroxine was started and patient improved completely within eight weeks. Hypothyroidism can present with ataxia as presenting feature. Hypothyroidism should be considered in all cases of cerebellar ataxia as it is a reversible cause of ataxia. PMID:26886095

  9. High ω3-polyunsaturated fatty acids in fat-1 mice prevent streptozotocin-induced Purkinje cell degeneration through BDNF-mediated autophagy

    OpenAIRE

    Dong Ho Bak; Enji Zhang; Min-Hee Yi; Do-Kyung Kim; Kyu Lim; Jwa-Jin Kim; Dong Woon Kim

    2015-01-01

    Loss of Purkinje cells has been implicated in the development of diabetic neuropathy, and this degeneration is characterized by impairment of autophagic processes. We evaluated whether fat-1 transgenic mice, a well-established animal model that endogenously synthesizes ω3 polyunsaturated fatty acids (ω3-PUFA), are protected from Purkinje cell degeneration in streptozotocin (STZ)-treated model with fat-1 mice. STZ-treated fat-1 mice did not develop hyperglycemia, motor deficits, or Purkinje ce...

  10. Metastasis suppressor 1 regulates neurite outgrowth in primary neuron cultures.

    Science.gov (United States)

    Yu, Juan; Lin, Shuyun; Wang, Mei; Liang, Lijun; Zou, Zijiao; Zhou, Xinfeng; Wang, Meichi; Chen, Ping; Wang, Ying

    2016-10-01

    Metastasis suppressor 1 (MTSS1) or missing in metastasis (MIM) is an actin- and membrane-binding protein with tumor suppressor functions. MTSS1 is important for cell morphology, motility, metastasis. The role of MTSS1 in cell morphology has been widely investigated in non-neuronal tissues; however the role of MTSS1 in neurite outgrowth remains unclear. Here we investigated the effect of MTSS1 on neurite outgrowth in primary cerebellar granule and hippocampal neurons of mouse. We found that overexpression of MTSS1 in cerebellar granule neurons significantly enhanced dendrite elaboration but inhibited axon elongation. This phenotype was significantly reduced by deletion of the Wiskott-Aldrich homology 2 (WH2) motif and point mutation in the insulin receptor substrate p53 (IRSp53) and MIM/MTSS1 homology (IMD) domain. Furthermore, inhibition of Rac1 activity or blocking of phosphatidyl inositol phosphates (PIPs) signaling decreased the effect of MTSS1 markedly. In accordance with the over-expression data, knockdown of MTSS1 in cerebellar granule neurons could increase the axon length but decrease the dendrite length and the number of dendrites. In addition, MTSS1 knock down in embryonic hippocampal neurons suppressed neurite branching and reduced dendrite length. Our findings have demonstrated that MTSS1 modulates neuronal morphology, possibly through a Rac1-PIPs signaling pathway. PMID:27401056

  11. Cerebellar and cerebral atrophy in trichothiodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hye-Kyung; Sargent, Michael A.; Poskitt, Kenneth J. [British Columbia Children' s Hospital, Department of Radiology, Vancouver, BC (Canada); Prendiville, Julie S. [British Columbia Children' s Hospital, Division of Paediatric Dermatology, Department of Paediatrics, Vancouver, BC (Canada)

    2005-10-01

    Trichothiodystrophy is a rare neuroectodermal disorder of autosomal recessive inheritance that is characterized by brittle hair, nail dysplasia, ichthyosis, mental retardation, and gonadal failure. We describe a female patient whose cranial MRI revealed almost total lack of myelination in the supratentorial white matter, which is similar to the previously described cases. In addition, there was progressive cerebellar and cerebral atrophy, which has not been well documented in association with trichothiodystrophy. (orig.)

  12. Hereditary spastic paraplegia with cerebellar ataxia

    DEFF Research Database (Denmark)

    Nielsen, J E; Johnsen, B; Koefoed, P;

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unip...... relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations....

  13. Vestibular Neuronitis

    Science.gov (United States)

    ... Prevent Painful Swimmer's Ear Additional Content Medical News Vestibular Neuronitis By Lawrence R. Lustig, MD NOTE: This ... Drugs Herpes Zoster Oticus Meniere Disease Purulent Labyrinthitis Vestibular Neuronitis Vestibular neuronitis is a disorder characterized by ...

  14. The cellular state determines the effect of melatonin on the survival of mixed cerebellar cell culture.

    Directory of Open Access Journals (Sweden)

    Daiane Gil Franco

    Full Text Available The constitutive activation of nuclear factor-κB (NF-κB, a key transcription factor involved in neuroinflammation, is essential for the survival of neurons in situ and of cerebellar granule cells in culture. Melatonin is known to inhibit the activation of NF-κB and has a cytoprotective function. In this study, we evaluated whether the cytoprotective effect of melatonin depends on the state of activation of a mixed cerebellar culture that is composed predominantly of granule cells; we tested the effect of melatonin on cultured rat cerebellar cells stimulated or not with lipopolysaccharide (LPS. The addition of melatonin (0.1 nM-1 µM reduced the survival of naïve cells while inhibiting LPS-induced cell death. Melatonin (100 nM transiently (15 min inhibited the nuclear translocation of both NF-κB dimers (p50/p50, p50/RelA and, after 60 min, increased the activation of p50/RelA. Melatonin-induced p50/RelA activity in naïve cells resulted in the transcription of inducible nitric oxide synthase (iNOS and the production of NO. Otherwise, in cultures treated with LPS, melatonin blocked the LPS-induced activation of p50/RelA and the reduction in p50/p50 levels and inhibited iNOS expression and NO synthesis. Therefore, melatonin in vehicle-treated cells induces cell death, while it protects against LPS-induced cytotoxicity. In summary, we confirmed that melatonin is a neuroprotective drug when cerebellar cells are challenged; however, melatonin can also lead to cell death when the normal balance of the NF-κB pathway is disturbed. Our data provide a mechanistic basis for understanding the influence of cell context on the final output response of melatonin.

  15. Computed tomography in hypertensive cerebellar hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Nose, T.; Maki, Y.; Ono, Y.; Yoshizawa, T.; Tsuboi, K. (Tsukuba Univ., Sakura, Ibaraki (Japan))

    1981-11-01

    Fourteen cases of cerebellar hemorrhage were analysed from the point of CT-scan, and the following results were obtained. 1. The number of cases of cerebellar hemorrhage forms 4.4% of that of total intracranial hemorrhage. 2. Most of the cerebellar hematomas extend upward. Downward extension is rare. 3. In acute dead cases hematomas are 5 cm or more in diameter and lie over bilateral hemispheres with the extension to third or fourth ventricles in CT-scans. 4. Slowly progressive cases are detriorated by the secondary hydrocephalus. 5. In mild cases hematomas are 3cm or less in diameter on CT-scans and the hematoma evacuation is not indicated for these cases. 6. The shunt operation alone is sufficient for the life saving of the slowly progressive cases, but the hematoma evacuation is indicated in these cases if the functional prognosis is taken into consideration. 7. Immediate hematoma evacuation together with the ventricular drainage is considered to be effective for the life saving of the acute fulminant cases.

  16. Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor.

    OpenAIRE

    Rice, G P; Lesaux, J; Vandervoort, P.; Macewan, L; Ebers, G C

    1997-01-01

    It has been previously shown that ondansetron, a 5-HT3 antagonist, can ameliorate vertigo in patients with acute brainstem disorders. A coincidental benefit was the improvement of cerebellar tremor in some patients with both vertigo and tremor. To further evaluate this effect, a placebo controlled, double blind, crossover study was conducted of a single dose of intravenous ondansetron in 20 patients with cerebellar tremor caused by multiple sclerosis, cerebellar degeneration, or drug toxicity...

  17. Sensory mechanisms of balance control in cerebellar disease

    OpenAIRE

    Bunn, L. M.

    2011-01-01

    A wealth of evidence exists to suggest that the cerebellum has an important role in the integration of vestibular, proprioceptive and visual sensory signals. Human bipedal balance depends on sensory integration and balance impairment is a common feature of cerebellar disease. I test the hypothesis that disrupted sensori-motor processing is responsible for balance impairment in cerebellar disease. Balance control in subjects with pure cerebellar disease (SCA6) was compared with matched healthy...

  18. Lacunar thalamic stroke with pure cerebellar and proprioceptive deficits.

    OpenAIRE

    Gutrecht, J A; Zamani, A A; D N Pandya

    1992-01-01

    Case reports of two patients with cerebellar ataxia and proprioceptive sensory loss are presented. MRI of the brain revealed lesions of the ventroposterior part of the thalamus. These patients illustrate clinically the anatomical independence of cerebellar and sensory pathways in the thalamus. We suggest that the ataxic deficit is caused by interruption of cerebellar outflow pathways in the thalamus and not secondary to sensory deafferentation.

  19. Fast convergence of learning requires plasticity between inferior olive and deep cerebellar nuclei in a manipulation task: a closed-loop robotic simulation.

    Science.gov (United States)

    Luque, Niceto R; Garrido, Jesús A; Carrillo, Richard R; D'Angelo, Egidio; Ros, Eduardo

    2014-01-01

    The cerebellum is known to play a critical role in learning relevant patterns of activity for adaptive motor control, but the underlying network mechanisms are only partly understood. The classical long-term synaptic plasticity between parallel fibers (PFs) and Purkinje cells (PCs), which is driven by the inferior olive (IO), can only account for limited aspects of learning. Recently, the role of additional forms of plasticity in the granular layer, molecular layer and deep cerebellar nuclei (DCN) has been considered. In particular, learning at DCN synapses allows for generalization, but convergence to a stable state requires hundreds of repetitions. In this paper we have explored the putative role of the IO-DCN connection by endowing it with adaptable weights and exploring its implications in a closed-loop robotic manipulation task. Our results show that IO-DCN plasticity accelerates convergence of learning by up to two orders of magnitude without conflicting with the generalization properties conferred by DCN plasticity. Thus, this model suggests that multiple distributed learning mechanisms provide a key for explaining the complex properties of procedural learning and open up new experimental questions for synaptic plasticity in the cerebellar network.

  20. Fast convergence of learning requires plasticity between inferior olive and deep cerebellar nuclei in a manipulation task: a closed-loop robotic simulation

    Directory of Open Access Journals (Sweden)

    Niceto Rafael Luque

    2014-08-01

    Full Text Available The cerebellum is known to play a critical role in learning relevant patterns of activity for adaptive motor control, but the underlying network mechanisms are only partly understood. The classical long-term synaptic plasticity between parallel fibers and Purkinje cells, which is driven by the inferior olive (IO, can only account for limited aspects of learning. Recently, the role of additional forms of plasticity in the granular layer, molecular layer and deep cerebellar nuclei (DCN has been considered. In particular, learning at DCN synapses allows for generalization, but convergence to a stable state requires hundreds of repetitions. In this paper we have explored the putative role of the IO-DCN connection by endowing it with adaptable weights and exploring its implications in a closed-loop robotic manipulation task. Our results show that IO-DCN plasticity accelerates convergence of learning by up to two orders of magnitude without conflicting with the generalization properties conferred by DCN plasticity. Thus, this model suggests that multiple distributed learning mechanisms provide a key for explaining the complex properties of procedural learning and open up new experimental questions for synaptic plasticity in the cerebellar network.

  1. Cerebellar ataxia as the presenting manifestation of Lyme disease.

    Science.gov (United States)

    Arav-Boger, Ravit; Crawford, Thomas; Steere, Allen C; Halsey, Neal A

    2002-04-01

    A 7-year-old boy from suburban Baltimore who presented with cerebellar ataxia and headaches was found by magnetic resonance imaging to have multiple cerebellar enhancing lesions. He had no history of tick exposure. He was initially treated with steroids for presumptive postinfectious encephalitis. Lyme disease was diagnosed 10 weeks later after arthritis developed. Testing of the cerebrospinal fluid obtained at the time cerebellar ataxia was diagnosed revealed intrathecal antibody production to Borrelia burgdorferi. Treatment with intravenous antibiotics led to rapid resolution of persistent cerebellar findings.

  2. [Buspirone in the treatment of cerebellar ataxia].

    Science.gov (United States)

    Svetel, M; Vojvodić, N; Filipović, S R; Dragasević, N; Sternić, N; Kostić, V S

    1999-01-01

    Ataxia is defined as a disturbance which, quite independent of any motor weakness, alters direction and extent of voluntary movement and impairs the sustained voluntary of reflex muscle contraction necessary for maintaining postiue and equilibrium [1]. Since pathophysiological basis of cerebeller ataxia is still not completely clear, the current therapeutic attempts are mainly symptom-oriented [3]. One possible approach could be a modification of potentially involved neurotransmitter systems of the cerebellum, where particularly interesting is the serotonergic system. However, attempts with levorotatory form of tryptophan (5-HT precursors) proved to be ineffective [4, 5]. Since receptors in the cerebellum are mainly of 5-HTIA subtype, the use of specific agonists might be a more reasonable therapy [6]. The study initially involved 11 patients, but only 9 completed the protocol due to unfavorable side effects. Our open label prospective study lasted for 15 weeks. The patients were tested before the beginning of the treatment (initial visit), at 7th (first visit) and 11th week (second visit) of continuous therapy, and eventually at 15th week (final visit). The daily dose was 40 mg at the first and 60 mg at the second visit. We used the evaluation scale gurposed for cerebellar functions testing (speech, gait, coordination and ocular movements). Significant improvement of cerebellar ataxia in patients under buspiron therapy has been noted. We analyzed the results obtained from our 9 patients (4 females and 5 males), of which 6 patients suffered from cerebellar degeneration, one from multiple sclerosis, one from Ramsey-Hunt syndrome, and one from pontine myelinolysis. At the initial visit the patient score was 18.9 (SD = 7.3), subsequently, at the iirst visit the score was 15.4 (SD = 8), while the second visit yielded the score of 12.9 (SD = 8.2), and finally, after a two-weeks lasting wash-out period, it was 17.7 (SD = 7.1) (Table 1). It was found that patients

  3. Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures.

    Directory of Open Access Journals (Sweden)

    Jeppe Falsig

    Full Text Available Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic cerebellar slices (COCS experienced progressive spongiform neurodegeneration closely reproducing prion disease, with three different prion strains giving rise to three distinct patterns of prion protein deposition. Neurodegeneration did not occur when PrP was genetically removed from neurons, and a comprehensive pharmacological screen indicated that neurodegeneration was abrogated by compounds known to antagonize prion replication. Prion infection of COCS and mice led to enhanced fodrin cleavage, suggesting the involvement of calpains or caspases in pathogenesis. Accordingly, neurotoxicity and fodrin cleavage were prevented by calpain inhibitors but not by caspase inhibitors, whereas prion replication proceeded unimpeded. Hence calpain inhibition can uncouple prion replication from its neurotoxic sequelae. These data validate COCS as a powerful model system that faithfully reproduces most morphological hallmarks of prion infections. The exquisite accessibility of COCS to pharmacological manipulations was instrumental in recognizing the role of calpains in neurotoxicity, and significantly extends the collection of tools necessary for rigorously dissecting prion pathogenesis.

  4. Maternal exposure to a continuous 900-MHz electromagnetic field provokes neuronal loss and pathological changes in cerebellum of 32-day-old female rat offspring.

    Science.gov (United States)

    Odacı, Ersan; Hancı, Hatice; İkinci, Ayşe; Sönmez, Osman Fikret; Aslan, Ali; Şahin, Arzu; Kaya, Haydar; Çolakoğlu, Serdar; Baş, Orhan

    2016-09-01

    Large numbers of people are unknowingly exposed to electromagnetic fields (EMF) from wireless devices. Evidence exists for altered cerebellar development in association with prenatal exposure to EMF. However, insufficient information is still available regarding the effects of exposure to 900 megahertz (MHz) EMF during the prenatal period on subsequent postnatal cerebellar development. This study was planned to investigate the 32-day-old female rat pup cerebellum following exposure to 900MHz EMF during the prenatal period using stereological and histopathological evaluation methods. Pregnant rats were divided into control, sham and EMF groups. Pregnant EMF group (PEMFG) rats were exposed to 900MHz EMF for 1h inside an EMF cage during days 13-21 of pregnancy. Pregnant sham group (PSG) rats were also placed inside the EMF cage during days 13-21 of pregnancy for 1h, but were not exposed to any EMF. No procedure was performed on the pregnant control group (PCG) rats. Newborn control group (CG) rats were obtained from the PCG mothers, newborn sham group (SG) rats from the PSG and newborn EMF group (EMFG) rats from the PEMFG rats. The cerebellums of the newborn female rats were extracted on postnatal day 32. The number of Purkinje cells was estimated stereologically, and histopathological evaluations were also performed on cerebellar sections. Total Purkinje cell numbers calculated using stereological analysis were significantly lower in EMFG compared to CG (pprenatal exposure to EMF affects the development of Purkinje cells in the female rat cerebellum and that the consequences of this pathological effect persist after the postnatal period. PMID:26391347

  5. Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

    Science.gov (United States)

    Tran-Van-Minh, Alexandra; Abrahamsson, Therése; Cathala, Laurence; DiGregorio, David A

    2016-08-17

    Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging. We show that, while synaptic potentials summate sublinearly, concomitant dendritic calcium signals summate either linearly or supralinearly depending on the number of synapses activated. The supralinear dendritic calcium triggers a branch-specific, short-term suppression of neurotransmitter release that alters the pattern of synaptic activation. Thus, differential voltage and calcium integration permits dynamic regulation of neuronal input-output transformations without altering intrinsic nonlinear integration mechanisms.

  6. Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

    Science.gov (United States)

    Tran-Van-Minh, Alexandra; Abrahamsson, Therése; Cathala, Laurence; DiGregorio, David A

    2016-08-17

    Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging. We show that, while synaptic potentials summate sublinearly, concomitant dendritic calcium signals summate either linearly or supralinearly depending on the number of synapses activated. The supralinear dendritic calcium triggers a branch-specific, short-term suppression of neurotransmitter release that alters the pattern of synaptic activation. Thus, differential voltage and calcium integration permits dynamic regulation of neuronal input-output transformations without altering intrinsic nonlinear integration mechanisms. PMID:27537486

  7. The cerebellar Golgi cell and spatiotemporal organization of granular layer activity

    Directory of Open Access Journals (Sweden)

    Egidio eD‘Angelo

    2013-05-01

    Full Text Available The cerebellar granular layer has been suggested to perform a complex spatiotemporal reconfiguration of incoming mossy fiber signals. Central to this role is the inhibitory action exerted by Golgi cells over granule cells: Golgi cells inhibit granule cells through double feedforward and feedback inhibitory loops and generate a broad lateral inhibition that extends beyond the afferent synaptic field. This characteristic connectivity has recently been investigated in great detail and been correlated with specific functional properties of the neuron. These include theta-frequency pacemaking, network entrainment into coherent oscillations and phase resetting. Important advances have also been made in terms of determining the membrane and synaptic properties of the neuron, and clarifying the mechanisms of activation by input bursts. Moreover, voltage sensitive dye imaging and multi-electrode array recordings, combined with mathematical simulations based on realistic computational models, have improved our understanding of the impact of Golgi cell activity on granular layer circuit computations. These investigations have highlighted the critical role of Golgi cells in: generating dense clusters of granule cell activity organized in center-surround structures, implementing combinatorial operations on multiple mossy fiber inputs, regulating transmission gain and cut-off frequency, controlling spike timing and burst transmission, and determining the sign, intensity and extension of long-term synaptic plasticity at the mossy fiber-granule cell relay. This review considers recent advances in the field, highlighting the functional implications of Golgi cells for granular layer network computation and indicating new challenges for cerebellar research.

  8. The role of GABAC receptors in the regulation of cerebellar metabolism

    International Nuclear Information System (INIS)

    Full text: GABAC (γ-aminobutyric acid) receptors are characterised by their insensitivity to the GABAA-selective antagonist, bicuculline and the GABAB-selective agonist, baclofen. These receptors are composed of a homo- or hetero-oligomeric assembly of novel subunits termed ρ1 and ρ2. The subunit ρ1 is located mainly in the retina, although it has been identified in Purkinje cells of the cerebellum, whilst ρ2 is more widely expressed in the CNS (cerebellum, hippocampus and cortex). The functional role of these receptors has yet to be established. They may be involved in the regulation of the sleep-wake cycle, modulation of excitatory neurotransmitter release and in the inhibition of pre-synaptic calcium currents. The present study investigated the potential role of GABAC receptors in guinea pig cerebellar tissue slice metabolism by analysing the fate of 13C from [3-13C]pyruvate by NMR spectroscopy, in the absence (control) and presence (20 μM) of the GABAC selective antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methyl-phosphonic acid TPMPA). Net flux and fractional enrichment of Glu, GABA, Gln, Ala and Asp isotopomers was measured by NMR spectroscopy and the rate of efflux of amino acids into the buffer was estimated by HPLC. Net flux of 13C into Glu C3 and C4 significantly increased, but release of Glu into the buffer was decreased by TPMPA. There was no increase of net flux into Gln C4, and net flux into Ala C3 was decreased. These data suggest that TPMPA-sensitive GABAC receptors influence the release of neurotransmitter glutamate in the cerebellum

  9. Cerebellar neurohistology and behavioural effects of gongronema latifolium and Rauwolfia vomitoria in mice.

    Science.gov (United States)

    Ekong, Moses B; Peter, Mine D; Peter, Aniekan I; Eluwa, Mokutima A; Umoh, Idorenyin U; Igiri, Anozeng O; Ekanem, Theresa B

    2014-06-01

    Rauwolfia vomitoria and Gongronema latifolium are medicinal herbs used for the treatment of hypertension, malaria, mental and intestinal disorders. G. latifolium is known to prevent the side effects reported for R. vomitoria. Therefore we decided to investigate what effects a combination treatment of G. latifolium and R. vomitoria would have on mice. Thirty male mice weighing 15-26 g were divided into 4 groups of 6 mice each. Groups 2, 3 and 4 were the treatment groups, and were treated with 150 mg/kg of R. vomitoria root bark extract, 200 mg/kg of G. latifolium leaf extract, and combination of both extracts, respectively. The control group received 0.5 mL of 20% Tween. The treatments were by oral gavages and lasted for 7 days. The open field maze neurobehavioural test was performed on day 8 to ascertain locomotion, exploration and anxiety, and the animals were immediately sacrificed. Results indicate lower body weights, though no difference was seen in the brain weights and behavioural test parameters in the treatment groups compared with the control group. Neurohistology of the cerebellum showed slight hypertrophy of Purkinje cells, with brain matrix loss in treatment groups 2 and 3, but group 4 showed no apparent histopathology. The cellular population was higher, while the cellular sizes and total cellular areas were lower in all the treatment groups. This study showed that R. vomitoria root bark and G. latifolium leaf extracts may individually cause cerebellar cytoarchitecture changes, which may be prevented with the combination of both remedies.

  10. Neuroprotective Effect of Carnosine on Primary Culture of Rat Cerebellar Cells under Oxidative Stress.

    Science.gov (United States)

    Lopachev, A V; Lopacheva, O M; Abaimov, D A; Koroleva, O V; Vladychenskaya, E A; Erukhimovich, A A; Fedorova, T N

    2016-05-01

    Dipeptide carnosine (β-alanyl-L-histidine) is a natural antioxidant, but its protective effect under oxidative stress induced by neurotoxins is studied insufficiently. In this work, we show the neuroprotective effect of carnosine in primary cultures of rat cerebellar cells under oxidative stress induced by 1 mM 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH), which directly generates free radicals both in the medium and in the cells, and 20 nM rotenone, which increases the amount of intracellular reactive oxygen species (ROS). In both models, adding 2 mM carnosine to the incubation medium decreased cell death calculated using fluorescence microscopy and enhanced cell viability estimated by the MTT assay. The antioxidant effect of carnosine inside cultured cells was demonstrated using the fluorescence probe dichlorofluorescein. Carnosine reduced by half the increase in the number of ROS in neurons induced by 20 nM rotenone. Using iron-induced chemiluminescence, we showed that preincubation of primary neuronal cultures with 2 mM carnosine prevents the decrease in endogenous antioxidant potential of cells induced by 1 mM AAPH and 20 nM rotenone. Using liquid chromatography-mass spectrometry, we showed that a 10-min incubation of neuronal cultures with 2 mM carnosine leads to a 14.5-fold increase in carnosine content in cell lysates. Thus, carnosine is able to penetrate neurons and exerts an antioxidant effect. Western blot analysis revealed the presence of the peptide transporter PEPT2 in rat cerebellar cells, which suggests the possibility of carnosine transport into the cells. At the same time, Western blot analysis showed no carnosine-induced changes in the level of apoptosis regulating proteins of the Bcl-2 family and in the phosphorylation of MAP kinases, which suggests that carnosine could have minimal or no side effects on proliferation and apoptosis control systems in normal cells. PMID:27297901

  11. Differential Modulation of GABAA Receptors Underlies Postsynaptic Depolarization- and Purinoceptor-Mediated Enhancement of Cerebellar Inhibitory Transmission: A Non-Stationary Fluctuation Analysis Study

    Science.gov (United States)

    Ono, Yumie; Saitow, Fumihito; Konishi, Shiro

    2016-01-01

    Cerebellar GABAergic inhibitory transmission between interneurons and Purkinje cells (PCs) undergoes a long-lasting enhancement following different stimulations, such as brief depolarization or activation of purinergic receptors of postsynaptic PCs. The underlying mechanisms, however, are not completely understood. Using a peak-scaled non-stationary fluctuation analysis, we therefore aimed at characterizing changes in the electrophysiological properties of GABAA receptors in PCs of rat cerebellar cortex during depolarization-induced “rebound potentiation (RP)” and purinoceptor-mediated long-term potentiation (PM-LTP), because both RP and PM-LTP likely depend on postsynaptic mechanisms. Stimulation-evoked inhibitory postsynaptic currents (eIPSCs) were recorded from PCs in neonatal rat cerebellar slices. Our analysis showed that postsynaptic membrane depolarization induced RP of eIPSCs in association with significant increase in the number of synaptic GABAA receptors without changing the channel conductance. By contrast, bath application of ATP induced PM-LTP of eIPSCs with a significant increase of the channel conductance of GABAA receptors without affecting the receptor number. Pretreatment with protein kinase A (PKA) inhibitors, H-89 and cAMPS-Rp, completely abolished the PM-LTP. The CaMKII inhibitor KN-62 reported to abolish RP did not alter PM-LTP. These results suggest that the signaling mechanism underlying PM-LTP could involve ATP-induced phosphorylation of synaptic GABAA receptors, thereby resulting in upregulation of the channel conductance by stimulating adenylyl cyclase-PKA signaling cascade, possibly via activation of P2Y11 purinoceptor. Thus, our findings reveal that postsynaptic GABAA receptors at the interneuron-PC inhibitory synapses are under the control of two distinct forms of long-term potentiation linked with different second messenger cascades. PMID:26930485

  12. Differential Modulation of GABAA Receptors Underlies Postsynaptic Depolarization- and Purinoceptor-Mediated Enhancement of Cerebellar Inhibitory Transmission: A Non-Stationary Fluctuation Analysis Study.

    Directory of Open Access Journals (Sweden)

    Yumie Ono

    Full Text Available Cerebellar GABAergic inhibitory transmission between interneurons and Purkinje cells (PCs undergoes a long-lasting enhancement following different stimulations, such as brief depolarization or activation of purinergic receptors of postsynaptic PCs. The underlying mechanisms, however, are not completely understood. Using a peak-scaled non-stationary fluctuation analysis, we therefore aimed at characterizing changes in the electrophysiological properties of GABAA receptors in PCs of rat cerebellar cortex during depolarization-induced "rebound potentiation (RP" and purinoceptor-mediated long-term potentiation (PM-LTP, because both RP and PM-LTP likely depend on postsynaptic mechanisms. Stimulation-evoked inhibitory postsynaptic currents (eIPSCs were recorded from PCs in neonatal rat cerebellar slices. Our analysis showed that postsynaptic membrane depolarization induced RP of eIPSCs in association with significant increase in the number of synaptic GABAA receptors without changing the channel conductance. By contrast, bath application of ATP induced PM-LTP of eIPSCs with a significant increase of the channel conductance of GABAA receptors without affecting the receptor number. Pretreatment with protein kinase A (PKA inhibitors, H-89 and cAMPS-Rp, completely abolished the PM-LTP. The CaMKII inhibitor KN-62 reported to abolish RP did not alter PM-LTP. These results suggest that the signaling mechanism underlying PM-LTP could involve ATP-induced phosphorylation of synaptic GABAA receptors, thereby resulting in upregulation of the channel conductance by stimulating adenylyl cyclase-PKA signaling cascade, possibly via activation of P2Y11 purinoceptor. Thus, our findings reveal that postsynaptic GABAA receptors at the interneuron-PC inhibitory synapses are under the control of two distinct forms of long-term potentiation linked with different second messenger cascades.

  13. [Cerebellar Control of Ocular Movements: Application to the Topographical Diagnosis of Cerebellar Lesions].

    Science.gov (United States)

    Hirose, Genjiro

    2016-03-01

    Over the last decade, substantial information on cerebellar oculomotor control has been provided by the use of sophisticated neuroanatomical, neurophysiological, and imaging techniques. We now know that an intact cerebellum is a prerequisite for normal oculomotor performance. This review clarifies the current knowledge on structure-function correlations of the cerebellum in relation to ocular movements and allows them to be applied to topographical diagnosis of cerebellar lesions. The cerebellar regions most closely related to oculomotor function are: (1) the flocculus/paraflocculus for VOR suppression, cancellation, smooth pursuit eye movement and gaze-holding, (2) the nodulus/ventral uvula for velocity storage and low frequency prolonged vestibular response, and (3) the dorsal oculomotor vermis (declive VI, folium VII) and the posterior portion of the fastigial nucleus (fastigial oculomotor region) for saccades and smooth pursuit initiation. Symptomatically, defects in the flocculus/parflocculus cause saccadic pursuit, downbeat nystagmus, and impairments to visual suppression of the VOR. Lesions of the nodulus/uvula reveal as periodic alternating nystagmus. Lesions of the oculomotor vermis and the fastigial nucleus can induce saccadic dysmetria, while fastigial nucleus lesions may also cause ocular flutter/opsoclonus. A detailed knowledge of cerebellar anatomy and the physiology of eye movements enables localization of lesions to specific areas of the cerebellum. PMID:27001776

  14. A coupled 3D-1D numerical monodomain solver for cardiac electrical activation in the myocardium with detailed Purkinje network

    Science.gov (United States)

    Vergara, Christian; Lange, Matthias; Palamara, Simone; Lassila, Toni; Frangi, Alejandro F.; Quarteroni, Alfio

    2016-03-01

    We present a model for the electrophysiology in the heart to handle the electrical propagation through the Purkinje system and in the myocardium, with two-way coupling at the Purkinje-muscle junctions. In both the subproblems the monodomain model is considered, whereas at the junctions a resistor element is included that induces an orthodromic propagation delay from the Purkinje network towards the heart muscle. We prove a sufficient condition for convergence of a fixed-point iterative algorithm to the numerical solution of the coupled problem. Numerical comparison of activation patterns is made with two different combinations of models for the coupled Purkinje network/myocardium system, the eikonal/eikonal and the monodomain/monodomain models. Test cases are investigated for both physiological and pathological activation of a model left ventricle. Finally, we prove the reliability of the monodomain/monodomain coupling on a realistic scenario. Our results underlie the importance of using physiologically realistic Purkinje-trees with propagation solved using the monodomain model for simulating cardiac activation.

  15. Two new cases of anti-Ca (anti-ARHGAP26/GRAF autoantibody-associated cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Jarius Sven

    2013-01-01

    Full Text Available Abstract Recently, we discovered a novel serum and cerebrospinal fluid (CSF autoantibody (anti-Ca to Purkinje cells in a patient with autoimmune cerebellar ataxia (ACA and identified the RhoGTPase-activating protein 26 (ARHGAP26; alternative designations include GTPase regulator associated with focal adhesion kinase pp125, GRAF, and oligophrenin-1-like protein, OPHN1L as the target antigen. Here, we report on two new cases of ARHGAP26 autoantibody-positive ACA that were first diagnosed after publication of the index case study. While the index patient developed ACA following an episode of respiratory infection with still no evidence for malignancy 52 months after onset, neurological symptoms heralded ovarian cancer in one of the patients described here. Our finding of anti-Ca/anti-ARHGAP26 antibodies in two additional patients supports a role of autoimmunity against ARHGAP26 in the pathogenesis of ACA. Moreover, the finding of ovarian cancer in one of our patients suggests that anti-Ca/anti-ARHGAP26-positive ACA might be of paraneoplastic aetiology in some cases. In conclusion, testing for anti-Ca/anti-ARHGAP26 should be included in the diagnostic work-up of patients with ACA, and an underlying tumour should be considered in patients presenting with anti-Ca/ARHGAP26 antibody-positive ACA.

  16. Cerebellar disorders: clinical/radiologic findings and modern imaging tools.

    Science.gov (United States)

    Manto, Mario; Habas, Christophe

    2016-01-01

    Cerebellar disorders, also called cerebellar ataxias, comprise a large group of sporadic and genetic diseases. Their core clinical features include impaired control of coordination and gait, as well as cognitive/behavioral deficits usually not detectable by a standard neurologic examination and therefore often overlooked. Two forms of cognitive/behavioral syndromes are now well identified: (1) the cerebellar cognitive affective syndrome, which combines an impairment of executive functions, including planning and working memory, deficits in visuospatial skills, linguistic deficiencies such as agrammatism, and inappropriate behavior; and (2) the posterior fossa syndrome, a very acute form of cerebellar cognitive affective syndrome occurring essentially in children. Sporadic ataxias include stroke, toxic causes, immune ataxias, infectious/parainfectious ataxias, traumatic causes, neoplasias and paraneoplastic syndromes, endocrine disorders affecting the cerebellum, and the so-called "degenerative ataxias" (multiple system atrophy, and sporadic adult-onset ataxias). Genetic ataxias include mainly four groups of disorders: autosomal-recessive cerebellar ataxias, autosomal-dominant ataxias (spinocerebellar ataxias and episodic ataxias), mitochondrial disorders, and X-linked ataxias. In addition to biochemical studies and genetic tests, brain imaging techniques are a cornerstone for the diagnosis, clinicoanatomic correlations, and follow-up of cerebellar ataxias. Modern radiologic tools to assess cerebellar ataxias include: functional imaging studies, magnetic resonance spectroscopy, volumetric studies, and tractography. These complementary methods provide a multimodal appreciation of the whole long-range cerebellar network functioning, and allow the extraction of potential biomarkers for prognosis and rating level of recovery after treatment. PMID:27432679

  17. Acute cerebellar ataxia with human parvovirus B19 infection

    OpenAIRE

    Shimizu, Y; Ueno, T.; Komatsu, H.; Takada, H.; Nunoue, T.

    1999-01-01

    A 2 year old boy developed acute cerebellar ataxia in association with erythema infectiosum. During the disease, genomic DNA and antibodies against human parvovirus B19 were detected in serum but not in cerebrospinal fluid. Parvovirus B19 associated acute cerebellar ataxia might occur due to transient vascular reaction in the cerebellum during infection.



  18. Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Naidich, M.J.; Walker, M.T.; Han, G. [Northwestern University Feinberg School of Medicine, Department of Radiology, Chicago, Illinois (United States); Northwestern Memorial Hospital, Chicago, IL (United States); Gottardi-Littell, N.R. [Northwestern Memorial Hospital, Chicago, IL (United States); Northwestern University Feinberg School of Medicine, Department of Pathology, Chicago, Illinois (United States); Chandler, J.P. [Northwestern Memorial Hospital, Chicago, IL (United States); Northwestern University Feinberg School of Medicine, Department of Neurological Surgery, Chicago, Illinois (United States)

    2004-10-01

    We describe a case of cerebellar pleomorphic xanthoastrocytoma (PXA) occurring in a patient with neurofibromatosis type 1 (NF1). The histomorphology of this uncommon glial (astrocytic) neoplasm is discussed. The occurrence of this tumor within the posterior fossa is extremely rare. To our knowledge, this is the first reported case of a cerebellar PXA in a patient with NF1. (orig.)

  19. Cerebellar glioblastoma multiforme presenting as a cerebellopontine angle mass

    Directory of Open Access Journals (Sweden)

    Anupam Jindal

    2006-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a highly malignant brain tumour, which is exceedingly rare and such tumour presenting as cerebellopontine angle (CPA mass is even rarer. We here discuss the case of a 15-year-old girl who had cerebellar GBM presenting as CPA mass that resembled meningioma on CT scan and was managed successfully with minimal problems.

  20. Drug-induced cerebellar ataxia: a systematic review

    NARCIS (Netherlands)

    Gaalen, J. van; Kerstens, F.G.; Maas, R.P.P.W.M.; Harmark, L.; Warrenburg, B.P.C. van de

    2014-01-01

    BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMB

  1. Time estimation in Parkinson's disease and degenerative cerebellar disease

    NARCIS (Netherlands)

    Beudel, Martijin; Galama, Sjoukje; Leenders, Klaus L.; de Jong, Bauke M.

    2008-01-01

    With functional MRI, we recently identified fronto-cerebellar activations in predicting time to reach a target and basal ganglia activation in velocity estimation, that is, small interval assessment. We now tested these functions in patients with Parkinson's disease (PD) and degenerative cerebellar

  2. Cerebellar glioblastoma multiforme in an adult

    OpenAIRE

    Mattos João Paulo; Marenco Horacio Armando; Campos José Maria; Faria Andréa Vasconcellos; Queiroz Luciano de Souza; Borges Guilherme; Oliveira Evandro de

    2006-01-01

    Cerebellar glioblastoma multiforme (GBM) is a rare tumor. This is the third case published in Brazilian literature and, the last one has been described more than 15 years ago. The aggressive behavior of GBM prompts for fast treatment, which can be hampered by the fact that the diagnosis of GBM requires a high degree of suspicion. We describe a case of GBM in a 46 years old man. In conjunction, we present a literature review including particular issues, clinical data, advances in imaging studi...

  3. Cerebellar glioblastoma multiforme in an adult

    Directory of Open Access Journals (Sweden)

    Mattos João Paulo

    2006-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor. This is the third case published in Brazilian literature and, the last one has been described more than 15 years ago. The aggressive behavior of GBM prompts for fast treatment, which can be hampered by the fact that the diagnosis of GBM requires a high degree of suspicion. We describe a case of GBM in a 46 years old man. In conjunction, we present a literature review including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options and the behavior of such malignant tumor.

  4. GABA agonist promoted formation of low affinity GABA receptors on cerebellar granule cells is restricted to early development

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, G H; Schousboe, A;

    1988-01-01

    The ability of the GABA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) to promote formation of low affinity GABA receptors on cerebellar granule cells was tested using primary cultures of these neurons. Granule cells were exposed to THIP (150 microM) for 6 hr after......, respectively, 4, 7, 10 and 14 days in culture. It was found that THIP treatment of 4- and 7-day-old cultures led to formation of low affinity GABA receptors, whereas such receptors could not be detected after THIP treatment in the older cultures (10 and 14 days) in spite of the fact that these cultured granule...... cells expressed a high density of high affinity GABA receptors. It is concluded that the ability of THIP to promote formation of low affinity GABA receptors on cerebellar granule cells is restricted to an early developmental period....

  5. Expression of NR2B in cerebellar granule cells specifically facilitates effect of motor training on motor learning.

    Directory of Open Access Journals (Sweden)

    Jianwei Jiao

    Full Text Available It is believed that gene/environment interaction (GEI plays a pivotal role in the development of motor skills, which are acquired via practicing or motor training. However, the underlying molecular/neuronal mechanisms are still unclear. Here, we reported that the expression of NR2B, a subunit of NMDA receptors, in cerebellar granule cells specifically enhanced the effect of voluntary motor training on motor learning in the mouse. Moreover, this effect was characterized as motor learning-specific and developmental stage-dependent, because neither emotional/spatial memory was affected nor was the enhanced motor learning observed when the motor training was conducted starting at the age of 3 months old in these transgenic mice. These results indicate that changes in the expression of gene(s that are involved in regulating synaptic plasticity in cerebellar granule cells may constitute a molecular basis for the cerebellum to be involved in the GEI by facilitating motor skill learning.

  6. Dipeptide Piracetam Analogue Noopept Improves Viability of Hippocampal HT-22 Neurons in the Glutamate Toxicity Model.

    Science.gov (United States)

    Antipova, T A; Nikolaev, S V; Ostrovskaya, P U; Gudasheva, T A; Seredenin, S B

    2016-05-01

    Effect of noopept (N-phenylacetyl-prolylglycine ethyl ester) on viability of neurons exposed to neurotoxic action of glutamic acid (5 mM) was studied in vitro in immortalized mouse hippocampal HT-22 neurons. Noopept added to the medium before or after glutamic acid improved neuronal survival in a concentration range of 10-11-10-5 M. Comparison of the effective noopept concentrations determined in previous studies on cultured cortical and cerebellar neurons showed that hippocampal neurons are more sensitive to the protective effect of noopept. PMID:27265136

  7. Single-neuron diversity generated by Protocadherin-β cluster in mouse central and peripheral nervous systems

    Directory of Open Access Journals (Sweden)

    Keizo eHirano

    2012-08-01

    Full Text Available The generation of complex neural circuits depends on the correct wiring of neurons with diverse individual characteristics. To understand the complexity of the nervous system, the molecular mechanisms for specifying the identity and diversity of individual neurons must be elucidated. The clustered protocadherins (Pcdh in mammals consist of approximately 50 Pcdh genes (Pcdh-α, Pcdh-β, and Pcdh-γ that encode cadherin-family cell surface adhesion proteins. Individual neurons express a random combination of Pcdh-α and Pcdh-γ, whereas the expression patterns for the Pcdh-β genes, 22 one-exon genes in mouse, are not fully understood. Here we show that the Pcdh-β genes are expressed in a 3’-polyadenylated form in mouse brain. In situ hybridization using a pan-Pcdh-β probe against a conserved Pcdh-β sequence showed widespread labeling in the brain, with prominent signals in the olfactory bulb, hippocampus, and cerebellum. In situ hybridization with specific probes for individual Pcdh-β genes showed their expression to be scattered in Purkinje cells from P10 to P150. The scattered expression patterns were confirmed by performing a newly developed single-cell 3’-RACE analysis of Purkinje cells, which clearly demonstrated that the Pcdh-β genes are expressed monoallelically and combinatorially in individual Purkinje cells. Scattered expression patterns of individual Pcdh-β genes were also observed in pyramidal neurons in the hippocampus and cerebral cortex, neurons in the trigeminal and dorsal root ganglion, GABAergic interneurons, and cholinergic neurons. Our results extend previous observations of diversity at the single-neuron level generated by Pcdh expression and suggest that the Pcdh-β cluster genes contribute to specifying the identity and diversity of individual neurons.

  8. Computed tomographic features of cerebellar hemangioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Yong Lan; Ko, Young Tae; Kim, Ho Kyun [Kyung Hee University Hospital, Seoul (Korea, Republic of)

    1980-06-15

    Computed tomographic and angiographic findings of 6 proven cerebellar Hemangiotoma seen in this hospital during last 2 years were analyzed. The results were as follows: 1. Except one 14 years old female, all of them wee 37 to 48 years old males. 2. The operative findings of the tumors were 3 cystic tumors with mural nodules and 3 solid tumors. Computed tomographic findings were: 3. Of three cases of cystic cerebellar hemangiotomas, 2 cases revealed characteristic CT findings such as; a. In precontrast study, a well defined round lower density containing one isodense nodule in its periphery was seen in each case. The absorption coefficiency of each lower density was around 5 EMI unit. b. In post contrast study, the nodules were enhanced densely and homogeneously white the lower densities remain unchanged. 4. Of three cases of solid cerebella hemangiotoma, 2 cases revealed isodense mass suggested by mass effect such as displaced 4th ventricle and peripheral edema in precontrast study, while the remaining case revealed ill defined slightly high density with peripheral edema. In postcontrast study, the 2 isodense masses showed well circumscribed homogenous enhancement with central slight lower density in one of them, while high density mass revealed no enhancement at all. 5. The vertebral angiography performed in 5 cases revealed high vascular tumors with feeding arteries, draining veins and increased circulation time. 6. The tumor blushing seen in vertebral angiography was correlated to the postcontrast enhancement of solid tumors and mural nodules in cystic hemangioblastoma.

  9. Cerebellar ependymal cyst in a dog.

    Science.gov (United States)

    Wyss-Fluehmann, G; Konar, M; Jaggy, A; Vandevelde, M; Oevermann, A

    2008-11-01

    An 11-week-old, male, Staffordshire Bull Terrier had a history of generalized ataxia and falling since birth. The neurologic findings suggested a localization in the cerebellum. Magnetic resonance imaging of the brain was performed. In all sequences the area of the cerebellum was almost replaced by fluid isointense to cerebrospinal fluid. A complete necropsy was performed after euthanasia. Histologically, the lesion was characterized by extensive loss of cerebellar tissue in both hemispheres and vermis. Toward the surface of the cerebellar defect, the cavity was confined by ruptured and folded membranes consisting of a layer of glial fibrillary acidic (GFAP)-positive glial cells covered multifocally by epithelial cells. Some of these cells bore apical cilia and were cytokeratin and GFAP negative, supporting their ependymal origin. The histopathologic features of our case are consistent with the diagnosis of an ependymal cyst. Its glial and ependymal nature as demonstrated by histopathologic and immunohistochemical examination differs from arachnoid cysts, which have also been reported in dogs. The origin of these cysts remains controversial, but it has been suggested that they develop during embryogenesis subsequent to sequestration of developing neuroectoderm. We speculate that the cyst could have been the result of a pre- or perinatal, possibly traumatic, insult because hemorrhage, and tissue destruction had occurred. To our knowledge, this is the first description of an ependymal cyst in the veterinary literature.

  10. Remote cerebellar hemorrhage after lumbar spinal surgery

    Energy Technology Data Exchange (ETDEWEB)

    Cevik, Belma [Baskent University Faculty of Medicine, Department of Radiology, Fevzi Cakmak Cad. 10. sok. No: 45, Bahcelievler, Ankara 06490 (Turkey)], E-mail: belmac@baskent-ank.edu.tr; Kirbas, Ismail; Cakir, Banu; Akin, Kayihan; Teksam, Mehmet [Baskent University Faculty of Medicine, Department of Radiology, Fevzi Cakmak Cad. 10. sok. No: 45, Bahcelievler, Ankara 06490 (Turkey)

    2009-04-15

    Background: Postoperative remote cerebellar hemorrhage (RCH) as a complication of lumbar spinal surgery is an increasingly recognized clinical entity. The aim of this study was to determine the incidence of RCH after lumbar spinal surgery and to describe diagnostic imaging findings of RCH. Methods: Between October 1996 and March 2007, 2444 patients who had undergone lumbar spinal surgery were included in the study. Thirty-seven of 2444 patients were scanned by CT or MRI due to neurologic symptoms within the first 7 days of postoperative period. The data of all the patients were studied with regard to the following variables: incidence of RCH after lumbar spinal surgery, gender and age, coagulation parameters, history of previous arterial hypertension, and position of lumbar spinal surgery. Results: The retrospective study led to the identification of two patients who had RCH after lumbar spinal surgery. Of 37 patients who had neurologic symptoms, 29 patients were women and 8 patients were men. CT and MRI showed subarachnoid hemorrhage in the folia of bilateral cerebellar hemispheres in both patients with RCH. The incidence of RCH was 0.08% among patients who underwent lumbar spinal surgery. Conclusion: RCH is a rare complication of lumbar spinal surgery, self-limiting phenomenon that should not be mistaken for more ominous pathologic findings such as hemorrhagic infarction. This type of bleeding is thought to occur secondary to venous infarction, but the exact pathogenetic mechanism is unknown. CT or MRI allowed immediate diagnosis of this complication and guided conservative management.

  11. Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor.

    Science.gov (United States)

    Zanin, Juan Pablo; Abercrombie, Elizabeth; Friedman, Wilma J

    2016-07-19

    Cerebellar granule cell progenitors (GCP) proliferate extensively in the external granule layer (EGL) of the developing cerebellum prior to differentiating and migrating. Mechanisms that regulate the appropriate timing of cell cycle withdrawal of these neuronal progenitors during brain development are not well defined. The p75 neurotrophin receptor (p75(NTR)) is highly expressed in the proliferating GCPs, but is downregulated once the cells leave the cell cycle. This receptor has primarily been characterized as a death receptor for its ability to induce neuronal apoptosis following injury. Here we demonstrate a novel function for p75(NTR) in regulating proper cell cycle exit of neuronal progenitors in the developing rat and mouse EGL, which is stimulated by proNT3. In the absence of p75(NTR), GCPs continue to proliferate beyond their normal period, resulting in a larger cerebellum that persists into adulthood, with consequent motor deficits.

  12. Neural correlates of impaired emotional face recognition in cerebellar lesions.

    Science.gov (United States)

    Adamaszek, Michael; Kirkby, Kenneth C; D'Agata, Fedrico; Olbrich, Sebastian; Langner, Sönke; Steele, Christopher; Sehm, Bernhard; Busse, Stefan; Kessler, Christof; Hamm, Alfons

    2015-07-10

    Clinical and neuroimaging data indicate a cerebellar contribution to emotional processing, which may account for affective-behavioral disturbances in patients with cerebellar lesions. We studied the neurophysiology of cerebellar involvement in recognition of emotional facial expression. Participants comprised eight patients with discrete ischemic cerebellar lesions and eight control patients without any cerebrovascular stroke. Event-related potentials (ERP) were used to measure responses to faces from the Karolinska Directed Emotional Faces Database (KDEF), interspersed in a stream of images with salient contents. Images of faces augmented N170 in both groups, but increased late positive potential (LPP) only in control patients without brain lesions. Dipole analysis revealed altered activation patterns for negative emotions in patients with cerebellar lesions, including activation of the left inferior prefrontal area to images of faces showing fear, contralateral to controls. Correlation analysis indicated that lesions of cerebellar area Crus I contribute to ERP deviations. Overall, our results implicate the cerebellum in integrating emotional information at different higher order stages, suggesting distinct cerebellar contributions to the proposed large-scale cerebral network of emotional face recognition. PMID:25912431

  13. Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

    NARCIS (Netherlands)

    Ferdinandusse, S.; Zomer, A.W.M.; Komen, J.C.; van den Brink, C.; Thanos, M.; Hamers, F.P.T.; Wanders, R.J.A.T.; van der Saag, P.T.; Poll-The, B.T.; Brites, P.

    2008-01-01

    Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigm

  14. [A case of cerebral gigantism with cerebellar atrophy].

    Science.gov (United States)

    Kitazawa, K; Ikeda, M; Tsukagoshi, H

    1990-05-01

    A 37-year-old housewife, who had physical characteristics of cerebral gigantism, such as the tall stature, acromegaly, macrocephalia, high arched palate and antimongoloid slant, developed cerebellar ataxia and dysarthria. Her mother, uncle and grandmother were also reported to have slowly progressive gait disturbance. Her mother was also tall. Endocrinological studies failed to show any definite abnormality. CT and MRI revealed remarkable cerebellar atrophy. Though cerebral gigantism is often associated with clumsiness and incoordination, the etiology of the ataxia is poorly understood. This case indicates that the ataxia in cerebral gigantism may be, at least partly, caused by cerebellar atrophy. PMID:2401112

  15. Variant PTA Terminating in Cerebellar Artery, Associated with Multiple Aneurysms

    Directory of Open Access Journals (Sweden)

    Yeong Uk Hwang

    2016-01-01

    Full Text Available Persistent trigeminal artery (PTA is one of the remnant fetal anastomoses between the carotid artery and basilar artery. PTAs are classified according to angiographic appearance and various connection. Among them, those directly terminating in the cerebellar arteries are rare subtype. In addition, aneurysms of the PTA are unusual in the literature and have not previously accompanied this subtype of PTA connecting cerebellar artery. We present the first case of an aneurysm of the PTA which is directly terminating in the cerebellar arteries and combined with multiple aneurysms.

  16. Variant PTA Terminating in Cerebellar Artery, Associated with Multiple Aneurysms.

    Science.gov (United States)

    Hwang, Yeong Uk; Kim, Jin Woo

    2016-01-01

    Persistent trigeminal artery (PTA) is one of the remnant fetal anastomoses between the carotid artery and basilar artery. PTAs are classified according to angiographic appearance and various connection. Among them, those directly terminating in the cerebellar arteries are rare subtype. In addition, aneurysms of the PTA are unusual in the literature and have not previously accompanied this subtype of PTA connecting cerebellar artery. We present the first case of an aneurysm of the PTA which is directly terminating in the cerebellar arteries and combined with multiple aneurysms. PMID:27446623

  17. Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome.

    Science.gov (United States)

    Bodranghien, Florian; Bastian, Amy; Casali, Carlo; Hallett, Mark; Louis, Elan D; Manto, Mario; Mariën, Peter; Nowak, Dennis A; Schmahmann, Jeremy D; Serrao, Mariano; Steiner, Katharina Marie; Strupp, Michael; Tilikete, Caroline; Timmann, Dagmar; van Dun, Kim

    2016-06-01

    The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor

  18. Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis

    OpenAIRE

    Shields, Shannon D.; Butt, Richard P.; Dib-Hajj, Sulayman D; WAXMAN, STEPHEN G.

    2015-01-01

    Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS). We previously showed that sodium channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia and MS-like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of diseas...

  19. Acute ethanol exposure inhibits silencing of cerebellar Golgi cell firing induced by granule cell axon input

    Directory of Open Access Journals (Sweden)

    Paolo eBotta

    2014-02-01

    Full Text Available Golgi cells (GoCs are specialized interneurons that provide inhibitory input to granule cells in the cerebellar cortex. GoCs are pacemaker neurons that spontaneously fire action potentials, triggering spontaneous inhibitory postsynaptic currents in granule cells and also contributing to the generation tonic GABAA receptor-mediated currents in granule cells. In turn, granule cell axons provide feedback glutamatergic input to GoCs. It has been shown that high frequency stimulation of granule cell axons induces a transient pause in GoC firing in a type 2-metabotropic glutamate receptor (mGluR2-dependent manner. Here, we investigated the effect ethanol on the pause of GoC firing induced by high frequency stimulation of granule cell axons. GoC electrophysiological recordings were performed in parasagittal cerebellar vermis slices from postnatal day 23 to 26 rats. Loose-patch cell-attached recordings revealed that ethanol (40 mM reversibly decreases the pause duration. An antagonist of mGluR2 reduced the pause duration but did not affect the effect of ethanol. Whole-cell voltage-clamp recordings showed that currents evoked by an mGluR2 agonist were not significantly affected by ethanol. Perforated-patch experiments in which hyperpolarizing and depolarizing currents were injected into GoCs demonstrated that there is an inverse relationship between spontaneous firing and pause duration. Slight inhibition of the Na+/K+ pump mimicked the effect of ethanol on pause duration. In conclusion, ethanol reduces the granule cell axon-mediated feedback mechanism by reducing the input responsiveness of GoCs. This would result in a transient increase of GABAA receptor-mediated inhibition of granule cells, limiting information flow at the input stage of the cerebellar cortex.

  20. Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.

    Directory of Open Access Journals (Sweden)

    Kate Kosmac

    2013-03-01

    Full Text Available Infection of the developing fetus with human cytomegalovirus (HCMV is a major cause of central nervous system disease in infants and children; however, mechanism(s of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.

  1. Hedgehog Signaling Modulates the Release of Gliotransmitters from Cultured Cerebellar Astrocytes.

    Science.gov (United States)

    Okuda, Hiroaki; Tatsumi, Kouko; Morita-Takemura, Shoko; Nakahara, Kazuki; Nochioka, Katsunori; Shinjo, Takeaki; Terada, Yuki; Wanaka, Akio

    2016-02-01

    Sonic hedgehog (Shh), a member of the Hedgehog (Hh) family, plays essential roles in the development of the central nervous system. Recent studies suggest that the Hh signaling pathway also functions in mature astrocytes under physiological conditions. We first examined the expression of genes encoding Hh signaling molecules in the adult mouse cerebellum by in situ hybridization histochemistry. mRNA for Patched homolog 1 (Ptch1), a receptor for Hh family members, was expressed in S100β-positive astrocytes and Shh mRNA was expressed in HuC/D-positive neurons, implying that the Hh signaling pathway contributes to neuro-glial interactions. To test this hypothesis, we next examined the effects of recombinant SHH N-terminal protein (rSHH-N) on the functions of cultured cerebellar astrocytes. rSHH-N up-regulated Hh signal target genes such as Ptch1 and Gli-1, a key transcription factor of the Hh signaling pathway. Although activation of Hh signaling by rSHH-N or purmorphamine influenced neither glutamate uptake nor gliotransmitters release, inhibition of the Hh signaling pathway by cyclopamine, neutralizing antibody against SHH or intracellular Ca(2+) chelation decreased glutamate and ATP release from cultured cerebellar astrocytes. On the other hand, cyclopamine, neutralizing antibody against SHH or Ca(2+) chelator hardly affected D-serine secretion. Various kinase inhibitors attenuated glutamate and ATP release, while only U0126 reduced D-serine secretion from the astrocytes. These results suggested that the Hh signaling pathway sustains the release of glutamate and ATP and participates in neuro-glial interactions in the adult mouse brain. We also propose that signaling pathways distinct from the Hh pathway govern D-serine secretion from adult cerebellar astrocytes. PMID:26694649

  2. Hereditary Cerebellar Ataxias: A Korean Perspective

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    Ji Sun Kim

    2015-05-01

    Full Text Available Hereditary ataxia is a heterogeneous disorder characterized by progressive ataxia combined with/without peripheral neuropathy, extrapyramidal symptoms, pyramidal symptoms, seizure, and multiple systematic involvements. More than 35 autosomal dominant cerebellar ataxias have been designated as spinocerebellar ataxia, and there are 55 recessive ataxias that have not been named systematically. Conducting genetic sequencing to confirm a diagnosis is difficult due to the large amount of subtypes with phenotypic overlap. The prevalence of hereditary ataxia can vary among countries, and estimations of prevalence and subtype frequencies are necessary for planning a diagnostic strategy in a specific population. This review covers the various hereditary ataxias reported in the Korean population with a focus on the prevalence and subtype frequencies as the clinical characteristics of the various subtypes.

  3. Performance of genetically-colorblind individuals on a rapid dark adaptation test based on the Purkinje shift.

    Science.gov (United States)

    Kim, V; Solomons, N W

    1983-02-01

    An experiment was conducted to determine whether or not genetic colorblindness would limit performance on a rapid dark adaptation test (RDAT) which is based on the Purkinje shift in retinal sensitivity to lower wavelengths of light energy under mesopic/scotopic conditions of illumination. No differences in RDAT performance between age-equivalent colorblind and non-colorblind subjects was observed. PMID:6601793

  4. Prophylactic role of melatonin against radiation induced damage in mouse cerebellum with special reference to Purkinje cells

    Energy Technology Data Exchange (ETDEWEB)

    Sisodia, Rashmi; Kumari, Seema; Verma, Rajesh Kumar; Bhatia, A L [Neurobiology Laboratory, Department of Zoology, University of Rajasthan, Jaipur 302004 (India)

    2006-06-15

    Melatonin, a hormone with a proven antioxidative efficacy, crosses all morphophysiological barriers, including the blood-brain barrier, and distributes throughout the cell. The present study is an attempt to investigate the prophylactic influence of a chronic low level of melatonin against an acute radiation induced oxidative stress in the cerebellum of Swiss albino mice, with special reference to Purkinje cells. After 15 days of treatment the mice were sacrificed at various intervals from 1 to 30 days. Biochemical parameters included lipid peroxidation (LPO) and glutathione (GSH) levels as the endpoints. The quantitative study included alterations in number and volume of Purkinje cells. Swiss albino mice were orally administered a very low dose of melatonin (0.25 mg/mouse/day) for 15 consecutive days before single exposure to 4 Gy gamma radiation. Melatonin checked the augmented levels of LPO, by approximately 55%, by day 30 day post-exposure. Radiation induced depleted levels of GSH could be raised by 68.9% by day 30 post-exposure. Radiation exposure resulted in a reduction of the volume of Purkinje cells and their total number. The administration of melatonin significantly protected against the radiation induced decreases in Purkinje cell volume and number. Results indicate the antioxidative properties of melatonin resulting in its prophylactic property against radiation induced biochemical and cellular alterations in the cerebellum. The findings support the idea that melatonin may be used as an anti-irradiation drug due to its potent free radical scavenging and antioxidative efficacy.

  5. Anomalous Cerebellar Anatomy in Chinese Children with Dyslexia.

    Science.gov (United States)

    Yang, Ying-Hui; Yang, Yang; Chen, Bao-Guo; Zhang, Yi-Wei; Bi, Hong-Yan

    2016-01-01

    The cerebellar deficit hypothesis for developmental dyslexia claims that cerebellar dysfunction causes the failures in the acquisition of visuomotor skills and automatic reading and writing skills. In people with dyslexia in the alphabetic languages, the abnormal activation and structure of the right or bilateral cerebellar lobes have been identified. Using a typical implicit motor learning task, however, one neuroimaging study demonstrated the left cerebellar dysfunction in Chinese children with dyslexia. In the present study, using voxel-based morphometry, we found decreased gray matter volume in the left cerebellum in Chinese children with dyslexia relative to age-matched controls. The positive correlation between reading performance and regional gray matter volume suggests that the abnormal structure in the left cerebellum is responsible for reading disability in Chinese children with dyslexia. PMID:27047403

  6. Cerebellar blood flow in methylmercury poisoning (Minamata disease)

    International Nuclear Information System (INIS)

    We looked at regional cerebellar blood flow in patients with Minamata disease (MD) using technetium-99 m ethyl cysteinate dimer (99m-Tc-ECD). We carried out single-photon emission computed tomography (SPECT) on 15 patients with MD (eight men, seven women, aged 51-78 years, mean 70.5 years) and 11 control subjects (eight men, three women, aged 62-80 years, mean 72.5 years). Regional blood flow was measured in the superior, middle, and inferior portions of the cerebellar hemispheres, and the frontal, temporal and occipital cerebral lobes. The degree of cerebellar atrophy was assessed on MRI. There were significant differences in regional blood flow in all parts of the cerebellum between patients and control, but no significant decrease was observed in the cerebrum. Blood flow was lower in the inferior cerebellum than in the other parts. Even in patients without cerebellar atrophy, flow was significantly decreased regional blood flow in the inferior part. (orig.)

  7. Anomalous cerebellar anatomy in Chinese children with dyslexia

    Directory of Open Access Journals (Sweden)

    Ying-Hui eYang

    2016-03-01

    Full Text Available The cerebellar deficit hypothesis for developmental dyslexia (DD claims that cerebellar dysfunction causes the failures in the acquisition of visuomotor skills and automatic reading and writing skills. In people with dyslexia in the alphabetic languages, the abnormal activation and structure of the right or bilateral cerebellar lobes have been identified. Using a typical implicit motor learning task, however, one neuroimaging study demonstrated the left cerebellar dysfunction in Chinese children with dyslexia. In the present study, using voxel-based morphometry, we found decreased gray matter volume in the left cerebellum in Chinese children with dyslexia relative to age-matched controls. The positive correlation between reading performance and regional gray matter volume suggests that the abnormal structure in the left cerebellum is responsible for reading disability in Chinese children with dyslexia.

  8. Cerebellar Hemangioblastoma and Von Hippel-Lindau Disease

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2002-02-01

    Full Text Available Six pediatric patients with cerebellar hemangioblastoma were screened for germline or somatic mutations of the von Hippel-Landau gene, in a study at Stanford University Medical Center, Palo Alto, CA.

  9. Bilateral cerebellar activation in unilaterally challenged essential tremor

    Directory of Open Access Journals (Sweden)

    Marja Broersma

    2016-01-01

    Conclusions: Our results expand on previous findings of bilateral cerebellar involvement in ET. We have identified specific areas in the bilateral somatomotor regions of the cerebellum: lobules V, VI and VIII.

  10. Cerebellar giant cell glioblastoma multiforme in an adult

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    Sudhansu Sekhar Mishra

    2014-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor that accounts for only 1% of all cases of GBM and its giant cell variant is even much rarely encountered in adults. A case of cerebellar giant cell GBM managed at our institution reporting its clinical presentation, radiological and histological findings, and treatment instituted is described. In conjunction, a literature review, including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options, and the behavior of such malignant tumor is presented. It is very important for the neurosurgeon to make the differential diagnosis between the cerebellar GBM, and other diseases such as metastasis, anaplastic astrocytomas, and cerebellar infarct because their treatment modalities, prognosis, and outcome are different.

  11. Unilateral absence of cerebellar hemisphere: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Erdogan, N.; Ozturk, O. [Department of Radiology, Erciyes University Faculty of Medicine, Kayseri (Turkey); Kocakoc, E. [Department of Radiology, Women' s Hospital, Sivas (Turkey); Bekar, D. [Department of Neurology, City Hospital, Sivas (Turkey)

    2002-01-01

    We describe a 38-year-old woman with absence of right cerebellar hemisphere incidentally discovered by MR imaging. No cerebellar abnormality was detected on neurological examination. Tissue probably representing dysgenetic cerebellar tissue with no corticomedullary differentiation was present, connected to the right superior cerebellar peduncle. Ipsilateral enlargement of the pons and cerebral peduncle were additional findings. Although the terms ''aplasia'' or ''agenesis'' have been used to describe this entity, intrauterine destruction is the presumed pathogenetic mechanism in our case, and therefore these terms have been avoided. Asymmetry of pons and mesencephalon may be related to compensatory reorganisation or to the impairment of sequential development of nuclei and neural tracts. (orig.)

  12. Cerebellar infarct patterns: The SMART-Medea study

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    Laurens J.L. De Cocker, MD

    2015-01-01

    Conclusions: Small cerebellar infarcts proved to be much more common than larger infarcts, and preferentially involved the cortex. Small cortical infarcts predominantly involved the posterior lobes, showed sparing of subcortical white matter and occurred in characteristic topographic patterns.

  13. Adult-onset cerebellar Ataxia: a clinical and genetic Survey

    NARCIS (Netherlands)

    E. Brusse (Esther)

    2011-01-01

    textabstractCerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Two main categories are distinguished: hereditary and sporadic ataxias. Sporadic ataxias may be symptomatic or idiopathic. The clinical classification of hereditary ataxias is nowadays being replaced by an

  14. Back to front: cerebellar connections and interactions with the prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Thomas C Watson

    2014-02-01

    Full Text Available Although recent neuroanatomical evidence has demonstrated closed-loop connectivity between prefrontal cortex and the cerebellum, the physiology of cerebello-cerebral circuits and the extent to which cerebellar output modulates neuronal activity in neocortex during behavior remain relatively unexplored. We show that electrical stimulation of the contralateral cerebellar fastigial nucleus (FN in awake, behaving rats evokes distinct local field potential (LFP responses (onset latency ~13 ms in the prelimbic (PrL subdivision of the medial prefrontal cortex. Trains of FN stimulation evoke heterogeneous patterns of response in putative pyramidal cells in frontal and prefrontal regions in both urethane-anaesthetized and awake, behaving rats. However, the majority of cells showed decreased firing rates during stimulation and subsequent rebound increases; more than 90% of cells showed significant changes in response. Simultaneous recording of on-going LFP activity from FN and PrL while rats were at rest or actively exploring an open field arena revealed significant network coherence restricted to the theta frequency range (5-10 Hz. Granger causality analysis indicated that this coherence was significantly directed from cerebellum to PrL during active locomotion. Our results demonstrate the presence of a cerebello-prefrontal pathway in rat and reveal behaviorally dependent coordinated network activity between the two structures, which could facilitate transfer of sensorimotor information into ongoing neocortical processing during goal directed behaviors.

  15. Real-World-Time Simulation of Memory Consolidation in a Large-Scale Cerebellar Model.

    Science.gov (United States)

    Gosui, Masato; Yamazaki, Tadashi

    2016-01-01

    We report development of a large-scale spiking network model of the cerebellum composed of more than 1 million neurons. The model is implemented on graphics processing units (GPUs), which are dedicated hardware for parallel computing. Using 4 GPUs simultaneously, we achieve realtime simulation, in which computer simulation of cerebellar activity for 1 s completes within 1 s in the real-world time, with temporal resolution of 1 ms. This allows us to carry out a very long-term computer simulation of cerebellar activity in a practical time with millisecond temporal resolution. Using the model, we carry out computer simulation of long-term gain adaptation of optokinetic response (OKR) eye movements for 5 days aimed to study the neural mechanisms of posttraining memory consolidation. The simulation results are consistent with animal experiments and our theory of posttraining memory consolidation. These results suggest that realtime computing provides a useful means to study a very slow neural process such as memory consolidation in the brain.

  16. Real-World-Time Simulation of Memory Consolidation in a Large-Scale Cerebellar Model.

    Science.gov (United States)

    Gosui, Masato; Yamazaki, Tadashi

    2016-01-01

    We report development of a large-scale spiking network model of the cerebellum composed of more than 1 million neurons. The model is implemented on graphics processing units (GPUs), which are dedicated hardware for parallel computing. Using 4 GPUs simultaneously, we achieve realtime simulation, in which computer simulation of cerebellar activity for 1 s completes within 1 s in the real-world time, with temporal resolution of 1 ms. This allows us to carry out a very long-term computer simulation of cerebellar activity in a practical time with millisecond temporal resolution. Using the model, we carry out computer simulation of long-term gain adaptation of optokinetic response (OKR) eye movements for 5 days aimed to study the neural mechanisms of posttraining memory consolidation. The simulation results are consistent with animal experiments and our theory of posttraining memory consolidation. These results suggest that realtime computing provides a useful means to study a very slow neural process such as memory consolidation in the brain. PMID:26973472

  17. The Intracellular Signaling Molecule Darpp-32 Is a Marker for Principal Neurons in the Cerebellum and Cerebellum-Like Circuits of Zebrafish

    Science.gov (United States)

    Robra, Lena; Thirumalai, Vatsala

    2016-01-01

    The dopamine and cAMP regulated phosphoprotein of apparent molecular weight 32 kDa (Darpp-32) is an inhibitory subunit of protein phosphatase-1 (PP-1). Darpp-32 activity is regulated by multiple ligand-activated G-protein coupled receptors (GPCRs). This protein is coded for by the protein phosphatase-1 regulatory subunit 1b (ppp1r1b) gene. Here, we provide experimental evidence for the presence of multiple isoforms of ppp1r1b in zebrafish. We show that these isoforms are differentially expressed during development with the full-length isoform being maternally deposited. Next, with a custom polyclonal antibody generated against the full-length protein, we show that in the adult, Darpp-32 is strongly expressed in principal neurons of the cerebellum and cerebellum-like circuits. These include Purkinje neurons in the cerebellum, Type-I neurons in the optic tectum, and crest cells in the medial octavolateralis nucleus (MON). We confirmed the identity of these neurons through their colocalization with Parvalbumin 7 immunoreactivity. Darpp-32 is seen in the somata and dendrites of these neurons with faint staining in the axons. In all of these regions, Darpp-32-immunoreactive cells were in close proximity to tyrosine hydroxylase (TH) immunoreactive puncta indicating the presence of direct catecholaminergic input to these neurons. Darpp-32 immunoreactivity was seen in Purkinje neurons as early as 3 days post-fertilization (dpf) when Purkinje neurons are first specified. In sum, we show that Darpp-32, a signaling integrator, is a specific marker of principal neurons in the cerebellum and cerebellum-like circuits in zebrafish. PMID:27540357

  18. Impairments in motor coordination without major changes in cerebellar plasticity in the Tc1 mouse model of Down syndrome.

    Science.gov (United States)

    Galante, Micaela; Jani, Harsha; Vanes, Lesley; Daniel, Hervé; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Bliss, Timothy V P; Morice, Elise

    2009-04-15

    Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of human chromosome 21 (Hsa21). Recently, O'Doherty et al. [An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309 (2005) 2033-2037] generated a trans-species aneuploid mouse line (Tc1) that carries an almost complete Hsa21. The Tc1 mouse is the most complete animal model for DS currently available. Tc1 mice show many features that relate to human DS, including alterations in memory, synaptic plasticity, cerebellar neuronal number, heart development and mandible size. Because motor deficits are one of the most frequently occurring features of DS, we have undertaken a detailed analysis of motor behaviour in cerebellum-dependent learning tasks that require high motor coordination and balance. In addition, basic electrophysiological properties of cerebellar circuitry and synaptic plasticity have been investigated. Our results reveal that, compared with controls, Tc1 mice exhibit a higher spontaneous locomotor activity, a reduced ability to habituate to their environments, a different gait and major deficits on several measures of motor coordination and balance in the rota rod and static rod tests. Moreover, cerebellar long-term depression is essentially normal in Tc1 mice, with only a slight difference in time course. Our observations provide further evidence that support the validity of the Tc1 mouse as a model for DS, which will help us to provide insights into the causal factors responsible for motor deficits observed in persons with DS.

  19. The Clinical Differentiation of Cerebellar Infarction from Common Vertigo Syndromes

    OpenAIRE

    Nelson, James A.; Viirre, Erik

    2009-01-01

    This article summarizes the emergency department approach to diagnosing cerebellar infarction in the patient presenting with vertigo. Vertigo is defined and identification of a vertigo syndrome is discussed. The differentiation of common vertigo syndromes such as benign paroxysmal positional vertigo, Meniere’s disease, migrainous vertigo, and vestibular neuritis is summarized. Confirmation of a peripheral vertigo syndrome substantially lowers the likelihood of cerebellar infarction, as do ind...

  20. Cerebellar Neuroblastoma in 2.5 Years Old Child

    OpenAIRE

    Pedram, Mohammad; Vafaie, Majid; Fekri, Kiavash; Haghi, Sabahat; Rashidi, Iran; Pirooti, Chia

    2013-01-01

    Neuroblastoma is the third most common malignancy of childhood, after leukemia and brain tumors. Only 2% of all neuroblastoma occur in the brain. Primary cerebellar neuroblastoma is an specific subset of Primitive Neuroectodermal Tumors (PNET). Meduloblastoma is a relatively common and well-established entity, consisting of primitive and multipotential cells that may exhibit some evidence of neuroblastic or gliad differentiation. But cerebellar neuroblastoma with ultrastractural evidence of s...